Radiation Therapy of Benign Diseases

Medical Radiology · Radiation Oncology
Series Editors: Nancy Y. Lee · Jiade J. Lu
David Roberge
Sarah S. Donaldson Editors
Radiation
Therapy
of Benign
Diseases
Third Edition
Medical Radiology
Radiation Oncology
Series Editors
Nancy Y. Lee
Jiade J. Lu
Medical Radiology - Radiation Oncology is a unique series that aims to
document the most innovative technologies in all fields within radiology,
thereby informing the physician in practice of the latest advances in diagnostic
and treatment techniques.
The contents range from contemporary statements relating to management

for various disease sites to explanations of the newest techniques for tumor
identification and of mechanisms for the enhancement of radiation effects,
with the emphasis on maximizing cure and minimizing complications.
Each volume is a comprehensive reference book on a topical theme, and the

editors are always experts of high international standing. Contributions are
included from both clinicians and researchers, ensuring wide appeal.
David Roberge • Sarah S. Donaldson
Editors
Radiation Therapy of
Benign Diseases
Third Edition
Editors
David Roberge Sarah S. Donaldson
Department of Radiation Oncology Department of Radiation Oncology
Centre Hospitalier de l’Université de Stanford Medicine
Montréal Palo Alto, CA, USA
Montreal, QC, Canada
ISSN 0942-5373 ISSN 2197-4187 (electronic)

Medical Radiology
ISSN 2731-4715
ISSN 2731-4723 (electronic)
Radiation Oncology
ISBN 978-3-031-35516-5 ISBN 978-3-031-35517-2 (eBook)

https://doi.org/10.1007/978-3-031-35517-2
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Prologue
In the mid-1980s, with the expansion of the use of ionizing radiation in the
treatment of oncologic and nononcologic disorders, the National Academy
of Science promoted a project to investigate this practice; the project pro-
duced the first edition of Radiation Therapy of Benign Diseases: A Clinical
Guide edited by Stanley E Order and Sarah S Donaldson, and published in
1990. The text pointed to the beneficial uses of radiation in specific nonma-
lignant conditions, discussed the risk/benefit of such management, and
offered caution about the inappropriate use of radiation therapy for certain
benign diseases. At that time, with the development of high energy medical
linear accelerators, standardization of units of radiation and nomenclature,
and increased understanding of the biology and physics of radiation, the
textbook on radiation therapy for benign disease became a functional addi-
tion to ones’ library and was widely referenced. In that era, the practice of
radiation for rare diseases was, in large part, based upon individual clini-
cians’ experiences. The Inter-Society Council for Radiation Oncology
(ISCRO), a multisocietal group representing leaders from the major
American radiation oncologic societies, with sponsorship from the American
College of Radiology, conducted a survey of 834 radiation oncologists with
a goal to exchange information underlying the use of radiation for a host of
nonmalignant conditions. Each benign disease in which radiation had been
utilized for management that was published in the English literature was
included in specific chapters of the textbook. The reader could easily refer-
ence a particular benign disorder, read a brief resume of the condition and
tables summarizing the published data, and refer to citations of pertinent
literature.
The second edition of the book, published in 1998, expanded the condi-
tions listed in the first edition. This benign disease text, intended to be a func-
tional workbook, became an easily accessible text for the occasion when a
practitioner was faced with the challenge of using radiation therapy for a rare,
nononcologic disease, in which the risk/benefit ratio required careful analy-
sis. A result from this major effort was a tabular consensus summarizing the
clinical uses of radiation therapy for these rare and difficult diseases. The
second edition of the book concluded with the statement “the text may never
be complete as new techniques, disorders and the definition of risk become
more clearly defined by clinical experience.” These words have proven to be
v
vi Prologue
true. Today, more than three decades later, with enhanced understanding of
the biology of both benign and malignant disease, and with greatly expanded
technical skills in the delivery of radiation, there is an even greater need to
update and expand our practical and clinical experience in a third and revised
edition of this clinical guide.
Preface
Readers of previous editions of Radiation Therapy of Benign Diseases will

notice changes in the format and substance of the work. Of course, as decades
have passed, new and updated references have been added to indications
which persisted in clinical use. The line between a malignant and a benign
process can sometimes be blurry, and indications well documented in oncol-
ogy textbooks and have been removed—low-grade astrocytoma as an exam-
ple. These losses left room for new and often exciting topics—whether it be
the treatment of refractory ventricular tachycardia or celiac pain.
Although some indications defy classification, alphabetical ordering has
been begrudgingly replaced by grouping in chapters by disease type. The
entries remain concise and focused on summary reports of the use of radia-
tion rather than attempting to educate the reader on the general aspects of a
disease process or delving into protracted debates on the pertinence of radia-
tion. Indications for which only isolated case reports could be found were
typically not considered. We have chosen to no longer include surveys which
may in the past have mislead readers as to the pertinence of radiotherapy in
specific indications.
Despite the longstanding history of radiotherapy in the management of
nononcological disease, the evidence supporting most indications is weak.
For many disease processes, it remains uncertain whether or not they are
modified by radiation. Randomized trials are rare and most evidence is in the
form of expert opinion based on small retrospective cohorts. In some cases,
this may be because the outcome is subjective (the pain of a heel spur) in
other cases because there are potential biases when assessment of the effect
of radiation requires a comparison to the natural history of the disease (is the
hemorrhage rate of a cavernoma reduced by radiation?). Even in those cases
where the link between radiation and the biological outcome is not in doubt,
that does not signify that the treatment improves the quantity or quality of life
vs. observation—witness the heated debate over treatment of asymptomatic
vascular malformations of the brain. In other cases, although radiotherapy
might have the postulated biological effect and the benefits might outweigh
the risks when compared to doing nothing, there is a preferred medical or
surgical alternative. For example, hormonal manipulation can improve the
life of women with hormone-sensitive breast cancer, but medication will be
preferred over pituitary radiosurgery.
The inclusion of a disease process in this textbook should not be inter-
preted as an endorsement of its treatment using ionizing radiation. In many
vii
viii Preface
cases, the reader might more appropriately view the inclusion as a historical
curiosity or a cautionary tale. As scientists, we should view available evi-
dence with skepticism and be supportive of prospective randomized trials—
powerful tools to either limit ineffective radiotherapy or to improve
accessibility to what may be underutilized and cost-effective treatments for
serious disease processes.
The final risk/benefit ratio in the treatment of an individual patient is deter-
mined by the physicians and the patient which must both often accept some
measure of uncertainty when making their decision. In this process, one
would be well advised to:
1. Determine the natural history of the benign disease. This may require
some humility that the radiation oncologist cannot be up to date in all
fields of medicine.
2. Have a clear vision of what would define success of a treatment—think in
more specific terms than “improvement” or “slowing.” Ensure that expec-
tations are in line with this definition of success. Some patients are desper-
ate, and we must safeguard them against inappropriate treatments.
3. Use this text and other source material to evaluate the evidence that radio-
therapy can lead to a successful outcome. When prospective comparative
data is not available, be mindful of how results can be colored by biases,
variability in the natural history of the disease process and the placebo
effect.
4. Educate yourself on the alternate treatments. How effective are they?
What evidence supports their efficacy? What are their associated risks and
toxicities? Why were these not considered?
5. Determine the potential long-term risks of radiation treatment. Consider
patient age, total dose, fractionation, the underlying organs at risk, as well
as any underlying disease. Beware of bias when weighing an uncertain
immediate benefit against future risks.
As a thought exercise, allow me to share the following abstract:

Background: Treatment of verrucae vulgares is sometimes difficult.
Invasive methods should not be used for young children.
Objective: Evaluation of a special X-ray therapy for treatment of verrucae
vulgares in children.
Methods: Nine children with warts on the hands and/or feet and in the face
were treated with X-ray treatment.
Results: Five children showed a complete remission of warts, 3 children a
partial remission. For 1 child, there was no response. On average, 3 treat-
ment sessions were needed for children showing a complete remission.
Conclusion: This therapy offers an easy-to-perform, alternative treatment
option. It is noninvasive and does not depend on special techniques.
Now I must confess to having altered the abstract. In fact, the actual
abstract described sham radiotherapy in the treatment of warts. After setting
aside the morality of lying to children and the design of the trial (which cer-
tainly does not prove that sham radiotherapy is any more effective than sim-
Preface ix
ple observation), take a moment to mentally replace warts with any other
disease for which you might be considering radiation. Next imagine how you
would receive a manuscript claiming results for sham radiotherapy equivalent
to those published for actual ionizing radiation. The unaltered 2002 abstract
describing treatment of verrucae vulgares is:
Background: Treatment of verrucae vulgares is sometimes difficult.
Invasive methods should not be used for young children.
Objective: Evaluation of a special suggestion therapy for treatment of ver-
rucae vulgares in children.
Methods: Nine children with warts on the hands and/or feet and in the face
were treated with a simulated X-ray treatment.
Results: Five children showed a complete remission of warts, 3 children a
partial remission. For 1 child, there was no response. On average, 3 treat-
ment sessions were needed for children showing a complete remission.
Conclusion: This therapy offers an easy-to-perform, alternative treatment
option. It is noninvasive and does not depend on special psychological tech-
niques for which training is required.
I wish to thank Dr. Donaldson for her support and trust. I wish to thank my
numerous collaborators for their diligence and patience. I wish to acknowl-
edge wordsmiths of previous editions whose work survived to the present. I
hope that this text, with its concise entries, will inform and intrigue the cur-
rent generation of radiation oncologists as much as the prior edition captured
my interest after a cashier at the McGill University bookstore failed to deter
me from spending what seemed to her an inappropriately large sum on such
a small book devoid of any color or illustrations.
Reference
• Meineke V, Reichrath J, Reinhold U, Tilgen W (2002) Verrucae vulgares

in children: successful simulated X-ray treatment (a suggestion-based
therapy). Dermatology 204(4):287–289. doi: 10.1159/000063360.
Montreal, QC, Canada David Roberge

Palo Alto, CA, USA Sarah S. Donaldson
Standard of Care
Physicians may have obligations related to their professional associations,

licensing authorities, employers, and local legal frameworks. The following
is a summary of important legal concepts in the physician-patient relationship
from the viewpoint of a North American lawyer with more than 42 years of
experience in the realm of healthcare.
Malpractice
Appellate courts have defined malpractice as the failure of a practitioner to

give and to exercise that degree of care as would be practiced by a reasonably
competent practitioner under the same or similar circumstances. Simply
stated, the appellate courts have recognized the existence of standards of care
followed by competent specialists in the various fields. Thus, malpractice is
found where a patient’s injury or death occurs as a result of a physician’s
failure to use diagnostic and/or treatment methods which would be followed
by the majority of competent physicians in the same field.
Informed Consent
Informed consent is a well-recognized duty and legal obligation of the doctor

in which he must disclose and provide adequate information to a patient for
him to give a consent and take an informed decision regarding personal and
life-changing health choices.
An informed consent is a consent where the patient has the adequate infor-
mation to make a decision on, for example, a treatment approach, surgery,
medication, radiotherapy, etc. In fact, the informed consent of the patient
touches every aspect of the medical relationship between the doctor and the
patient. It implies a communication between the patient and the healthcare
provider. It is a constant communication process in the medical relationship
where the doctor has the duty to keep the patient informed of any changes or
impressions that might change or affect the initial diagnosis, treatment
offered, and thus affect the consent or decision of the patient.
xi
xii Standard of Care
Moreover, it also touches the patient’s right to self-determination, to

decide what is right or wrong for him, to decide in accordance with his
beliefs, spirituality, and personal values. Even if the doctor considers a treat-
ment to be the best choice or decision for a patient’s health and does highly
recommend it, the right to accept or refuse a treatment remains a patient deci-
sion and must be respected. The doctor can recommend radiotherapy, but the
patient can still refuse it. The right to auto determination of one’s personal
body and choices is well recognized in society and in law. The patient has a
right to know and to have the information to make an informed decision.
Informed consent is also important to doctors regarding their legal liabil-
ity. Lawsuits are common in that matter. Doctors have an obligation to exer-
cise reasonable skill and judgment in treating patient, which is the standard of
care. This standard of care includes the duty to disclose the adequate informa-
tion so that the patient gives an informed consent.
Duty to Disclose
In the decision of the Supreme Court of Canada, Ciarlariello v. Schacter1, the

court establishes that the important element in the evaluation of medical lia-
bility of a doctor on the informed consent is to determine whether a reason-
able person in the patient’s position would want to know of the risk2.
In Hopp v. Lepp and in Reibl the Supreme Court of Canada establishes
that:
the relationship between doctor and patient gives rise to a duty to disclose
all materials risks, as well as to answer any specific questions posed by the
patient.
Therefore, in a medical liability suit on the informed consent of a patient,
the court will use an objective approach focusing on what a reasonable person
in the patient’s position would want to know to give an informed consent3.
Thus, experts will testify in front of the court on what risk should or should
not be disclosed to the patient, on the material risks, and thus regarding the
doctor breach on the duty of disclosure. The court has to look at the reason-
able patient in a similar position, while taking into consideration the specific
circumstances of the case. The court will then be able to respond to the ques-
tion of whether a reasonable person in the patient’s position would want to
know of the risk. Experts evidence regarding the risks that must be disclosed
and on the alternative treatments that could have been proposed to the patient
will certainly help the court to make a decision on the medical liability of the
doctor but will not be the only elements that the court will look at to decide
1
Ciarlariello c. Schacter, [1993] 2 R.C.S. 119
2
Ciarlariello v. Schacter, [1993] 2 R.C.S. 119
3
Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald
Robertson, 2007.
Standard of Care xiii
of the case issue4. The standard of disclosure is to inform the patient of the
risk that a reasonable patient would want to know.
It is established in the law that the doctors do not have to disclose every
single risk to a patient. ¨Only the risks which are characterized as material,
special, or unusual must be disclosed5¨. The court in Hopp v. Lepp also estab-
lishes that even if a certain risk is a mere possibility which ordinarily would
not need be disclosed, yet if its occurrence carries serious consequences, as
for example, paralysis or even death, it should be regarded as a material risk
requiring disclosure6. The doctor must explain the material, special, or
unusual risk and must explain the consequences if the risk were to material-
ize7. It is also important to note that in Hopp v. Lepp the court states that a
doctor must answer any specific question of a patient regarding the risks
involved of a proposed treatment8. In that sense, the question of the patient
must be specific. The question of the patient requires a discussion with the
doctor and a disclosure on some risks which normally would not need to be
disclosed.
The common risks associated with surgical treatments are considered by
the court as risks that do not necessarily need to be disclosed. The test of
reasonable person is used to determine what the patient would consider as a
general and common risk, for example, the risk of dying of anesthesia during
a surgery is considered as a common risk. However, the court will always
evaluate the specific circumstances of a case and the specific situation of the
patient, indeed a common risk for a given patient might be considered a spe-
cific risk for another patient with a health condition, predisposition, or physi-
cal or mental situation which increases the risk. Each case is different and
must be evaluated from the objective point of view of the reasonable patient.
The alternative treatments are part of the duty of disclosure of the doctor.
Thus, the doctor should inform the patient of alternative treatments that may
exist and explain the material, special, or unusual risks associated with the
treatment proposed and with the alternative’s treatments. The doctor can
explain and recommend one treatment over another and explain to the patient
his medical opinion. This gives the patient an opportunity to make a choice
knowing all the treatment possibilities and thus balancing the risks and
benefits.
4
Robertson, 2007, p.133.
5
6
Hopp v. Lepp, [1980] 2 R.C.S. 192. Legal liability of doctors and hospitals in Canada
fourth edition, Ellen I. Picard & Gerald Robertson, 2007.
7
8
Hopp v. Lepp, [1980] 2 R.C.S. 192. Legal liability of doctors and hospitals in Canada
fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.164.
xiv Standard of Care
he Uncertainty of a Treatment Effectiveness Proposed by

T
the Doctor
Medicine changes so fast; new treatments, medications, interventions,

devices… those are only examples of how medicine is constantly evolving. A
lot has changed in the medical field in the last years. This creates new chal-
lenges for doctors, regarding the uncertainty of a new treatment effectiveness
and uncertainty of the benefits and risks of a treatment. For example, when a
doctor pretends he did not know a risk that he should have disclosed normally
and for that reason the risk was not disclosed, the court will have to determine
if the doctor was negligent in not knowing of the risk. The court will apply the
test of the reasonable doctor as to determine if a reasonable doctor in similar
circumstances would probably have known of the risk. The law in general and
the interpretation of the law by the court are not static. It is always adapting
to new realities. New treatments for which the effectiveness is not yet deter-
mined in medical literature and for which doctors may be uncertain of the
chances of success are part of the duty to disclose as discussed in this text. In
that matter, doctors should disclose material, special, or unusual risks to the
patient regarding a new treatment and they should inform the patient of the
uncertainty regarding the effectiveness of the treatment proposed to allow the
patient to balance the risks and benefits.
In Nelson v. Patrick, a medical malpractice case, the patient alleged that the
defendant failed to obtain the informed consent by not disclosing the risks of
the radiation therapy9. The doctor recommended that the patient undergo
adjuvant radiotherapy after a total abdominal hysterectomy to reduce the risk
of cancer recurrence. Following the radiation treatments, the patient suffered
from injury to her bowel. The court gave a decision in favor of the patient
against the doctor.
Innovative Care
New equipment, tools, techniques, or procedures impact the standard of care.

Indeed, innovations in medicine imply the use of new technologies or treat-
ments at first by some members of the medical field but not by all. In specific
cases involving the use of innovative care: ¨the court must balance the desir-
ability of promoting advances in medical technology against the need to cau-
tion against resorting too readily to novel and untested treatment10¨. A series
of Alberta cases established that a doctor using a new technique or tool is
subject to a higher standard of care11. In Cryderman and Zimmer cases against
an obstetrician-gynecologist, the Alberta Court of Appeal emphasized that a
higher standard of care is required where a technique is innovative or experi-
9
Nelson v. Patrick, Court of Appeals of North Carolina, 1982.
10
11
Standard of Care xv
mental12. The Cryderman case was about the silver nitrate sterilization tech-
nique. The technique was invented and pioneered by the defendant in that
case. The Court stated that a higher standard of care was required and the fact
that the new technique was invented by the doctor elevated even more the
standard of care for that particular doctor. In Zimmer, the Court stated that
¨the experimental nature of the procedure required that the patient receive
careful and attentive after care as well as the fact that the patient must be
informed that the procedure is innovative or experimental.¨13 In both cases,
the doctor was considered not having met the standard of care.
Medical Research
When it comes to medical research, the patient’s consent plays a heavy and
very important role. ¨According to the Tri-Council Policy Statement, modern
research ethics require a favorable harms-benefits balance that is that the
foreseeable harms should not outweigh anticipated benefit14¨. A doctor who
conducts a research that has unreasonable balance between the harms and
benefits might be held liable for not meeting the standard of care, as of the
research ethics committee of an institution that accepts the research might
also be held responsible. In research and experimentation, a higher level of
disclosure of the information must be met by doctors. In the Halushka v.
University of Saskatchewan case a student participated in research for a test
of a new anesthetic15. The student was told the test was safe and that he should
not worry about anything. Thus, the student was not told that the research
implied a new drug, and he was not told about the risks. Unfortunately, during
the research he suffered from a cardiac arrest and had to be resuscitated. He
subsequently sued the doctors. The Court stated that when it comes to medi-
cal research the participant is entitled to a full disclosure of the risks, proba-
bilities, research information, and to the medical opinion that a reasonable
person would want to know before giving consent. In the Weiss v. Solomon
case, a patient underwent cataract surgery and agreed to participate in a
research study involving the use of ophthalmic drops and fluorescein angiog-
raphy16. When the angiography was performed, the patient experienced fatal
ventricular fibrillation. The Court stated that even if the risk was low, that it
should have been disclosed to the patient. The doctor and the hospital through
the research committee were found to be negligent in not disclosing the risk.
The Court stated that when it comes to the duty to inform in matters of scien-
12
13
Robertson, 2007, p.178 and 247.
14
Robertson, 2007, p.103é
15
Halushka v. University of Saskatchewan et al. 53 D.L.R. (2d) 436 (Sask. C.A.)
[Halushka] 1965.
16
Weiss v. Solomon, 1989, 48 C.C.L.T. 280 . Legal liability of doctors and hospitals in
Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.176.
xvi Standard of Care
tific research that all risks must be disclosed, even the risks that are rare,
especially if there are serious consequences17.
Standard of Care
The notion of standard of care refers to the conduct a doctor should have.
Doctors have an obligation to exercise reasonable skill and judgment in treat-
ing patient.
The criteria used by the court is to evaluate the conduct of a reasonable
doctor in the same or similar circumstances. Would he have acted that way?
This conduct must be analyzed taking into consideration all the circum-
stances. The court will evaluate the conduct of the doctor being sued by hav-
ing experts’ opinions on the specific medical field in which the doctor
practices. Thus, the court will evaluate if the doctor acted as a normal, pru-
dent practitioner of his medical field. For example, a radiologist will be com-
pared to other radiologists, to the conduct of a normal and prudent
radiologist.
The court will evaluate three elements in analyzing standard of care: the
education, experience and qualifications of the doctor, the degree of risk
involved in the procedure of treatment and the equipment, facilities, and
resources available to the doctor.
In Hazen v. Mullen, a judgment in favor of the plaintiff, it is a malpractice
case in administering radiotherapy. The judgment was reversed in Court of
appeal. The patient consulted the doctor for a tubercular adenitis and the doc-
tor recommended radiotherapy. As a result of the treatments the patient devel-
oped telangiectasia18. In court it was determined that the defendant possessed
the degree of skill and ability in their particular line of work, the X-ray treat-
ment was an appropriate treatment for the condition of the patient, and the
treatments were administered to the best of knowledge and skill of the doctor.
In 1929, it was decided by the Court of appeal that telangiectasia may occur
following radiotherapy and that there is no evidence that the doctor would
have been negligent in administrating the X-ray treatment. The doctor was
found to have exercised his best judgment and ability in treating the patient.
In Carver v. United States19, the plaintiff alleged that the physicians at
Letterman Army Medical Center (LAMC) negligently subjected him to
radiotherapy and acted below the standard of care which caused him injury.
In fact, the plaintiff alleged that the doctor administered radiotherapy without
having sufficient evidence of brain metastases, not having located a primary
tumor or had a biopsy performed of the lesions in the brain. As a result of the
radiotherapy, the plaintiff suffered cognitive decline. Eventually a diagnosis
of multiple sclerosis was suspected, and the patient was placed in a convales-
cent home. The Court concluded that the plaintiff failed to demonstrate that
17
18
Hazen v. Mullen, Court of Appeals of the District of Columbia, 1929.
19
Carver v. United States, United States District Court California, 1984.
Standard of Care xvii
the physicians acted below the standard of care in administrating radiother-

apy. In fact, the Court stated that the physicians balanced the risk of therapy
versus the risk of inaction, and that had judged that a biopsy was not indicated
and would be too risky.
Radiation Therapy Informed Consent Checklist
The consent should be obtained using simple, lay terminology.

1. Inform the patient about the benign disease or tumor and the region of the
body to be irradiated. Make certain that the patient understands the other
options of treatment and the desired benefit of the radiation to be given.
Do not assume that the patient has any prior understanding of the medi-
cal and/or surgical history of the disease or the reason for referral to the
radiation oncologist.
2. Explain the desired goal of the planned radiation.
3. Explain the number of treatments contemplated.
4. Describe the dose to be administered and probable effect on the disease
process as well as the effects of the treatment on the patient (i.e., nausea,
diarrhea, hair loss, etc.)
5. Try to arrange a meeting with patient and spouse or patient and parent so
that informed consent is understood by close family members.
6. Provide the opportunity for the patient to pose questions regarding the
treatment to be given and the goals of such treatment. Specifically ask:
Do you have any questions?
7. If the patient manifests uncertainty or confusion, strongly recommend a
second opinion prior to starting treatment.
8. Send a letter after meeting with the patient to the referring physician,
sending a copy to the patient as well. Legal counsel recommends outlin-
ing the treatment contemplated.
9. If the patient has past or present psychiatric history, obtain the patient’s
permission to send a copy of the letter to the patient’s psychiatrist in
addition to the referring physician.
10. Have a nurse, administrative assistant, or other witness present while the
informed consent is obtained, and have that individual witness the con-
sent form.
Acknowledgment
Stanley E. Order MD 1934–2013
We dedicate this third edition to Dr. Stanley E. Order, a true visionary and
idea-man recognized for innovation in Radiation Oncology.
Dr. Stanley (Stan) Order was born in Vienna, Austria, on November 1,
1934, and came to America as an infant when his parents migrated to avoid
Nazi aggressions. The family settled in Philadelphia where Stanley’s father
practiced medicine and where Stanley and his sister Sucha, also a physician
and radiation oncologist, were educated. Stanley attended Albright College
and Tufts Medical School. He began his medical training in pathology at the
Brigham Hospital in Boston but was inspired to pursue training in radiation
oncology at Yale, after fulfilling his military obligation. Stan was greatly influ-
enced by early pioneers in US medicine, particularly Dr. Byron Waksman,
who kindled his life-long interest in immunology, and powerful radiation
oncology leaders, Dr. Morton Kligerman, his chairman at Yale, and Dr. Samuel
Hellman, his chairman at the Harvard Joint Center for Radiation Oncology.
xix
xx Acknowledgment
In 1975, Dr. Order became the Chairman of the newly created Department
of Radiation Oncology at Johns Hopkins, where he continued his research
using radiolabeled antibodies for hepatoma and other challenging tumors.
Stan was truly a leader in radioimmunotherapy and recognized for his inno-
vative applications and novel administrations. In addition, he refined our
understanding of radiation therapy for benign diseases as the prime mover of
the first edition of the text Radiation Therapy of Benign Diseases, published
in 1993. Stan was ASTRO President 1988-89 and enjoyed worldwide recog-
nition. In 1991, he became head of the Institute for Systemic Therapy of
Cooper Hospital University Medical Center in Camden, New Jersey, where
he finished his active academic and clinical career. Dr. Stanley Order died on
January 19, 2013.
Stan was one of the most energetic and dedicated leaders of his time. He
was witty and always a major focus in every gathering. His distinctive per-
sonality was reinforced by his enormous handlebar mustache. Stan had many
interests beyond medicine, especially a love of fishing which he shared with
many colleagues and friends. A gifted innovator, Stan was principled in the
belief that “Technical excellence in radiation therapy is a standard, but com-
passion is what distinguishes a physician,” a quote he cited frequently. We
remember Dr. Stanley Order for his immunologic and technical advances to
radiation oncology, his compassion, and his drive to improve the outcome of
his patients, particularly those with the most challenging oncologic
problems.
Sarah S. Donaldson
Contents

Estimating the Risk of Radiation-Induced Malignancy
Following Radiotherapy for Benign Disease�� 1
Jean L. Nakamura, Steve E. Braunstein,
and Stephanie R. McKeown
Understanding Radiation Units�� 19
François De Blois
Autoimmune Disorders�� 27
Andrew Martella, Yushen Qian, and Rishabh Chaudhari
Dermatologic Conditions�� 55
Khalil Sultanem
Infectious Disease �� 61
David Roberge
Diseases of Inflammation�� 77
David Roberge
Endocrinological Disorders�� 89
Tyler Safran and Daniel Juneau
Musculoskeletal Disorders�� 105
David Y. Mak and Philip Wong
Neurological Disorders�� 181
Christian Iorio-Morin, Samuelle-Arianne Villeneuve,
Laurence Masson-Côté, and David Mathieu
Benign Lymphoid Disorders �� 191
Andrée-Anne Bernard
Pain Disorders�� 199
Christian Iorio-Morin, Samuelle-Arianne Villeneuve,
Psychiatric Disorders�� 211
M. Bret Schneider, Scott Soltys, and John R. Adler Jr
Reproduction�� 217
David Roberge
xxi
xxii Contents
Benign Tumors/Premalignant Conditions �� 229

Houda Bahig and David Roberge
Vascular Disorders�� 295
Luis Souhami
Other �� 321
Dominique Mathieu and Bill Loo
Estimating the Risk
of Radiation-Induced Malignancy
Following Radiotherapy
for Benign Disease
Jean L. Nakamura, Steve E. Braunstein,

and Stephanie R. McKeown
Contents 1 Introduction
1 Introduction 1
Throughout this textbook there are descriptions
2 Evidence Used in Estimation
of the Excess Risk of RIC Following
of a wide range of diseases treated typically with
MDRT 2 moderate-dose radiotherapy (MDRT; conven-
2.1 Mathematical Modeling and Phantom tionally fractionated dose range 5–40 Gy, mean
Studies 3 ~20 Gy). These regimens may provide clinical
2.2 Epidemiological Studies 3
2.3 Second Malignant Neoplasms in Patients
benefit in many of these situations with, for the
Exposed to HDRT for Cancer 4 most part, minimal acute side effects (Taylor
et al. 2015). The most important deterrent against
3 Tissues at Risk of RIC Following MDRT
for Benign Disease 5 the use of MDRT is often the acknowledged, if
3.1 Skin Cancer 5 normally very small, risk of a radiation-induced
3.2 Brain Cancer 6 cancer (RIC) many years after treatment
3.3 Thyroid Cancer 7
(McKeown et al. 2015; Mazonakis and Damilakis
3.4 Hematological Malignancies 8
3.5 Soft Tissue and Bone Cancer 9 2017). However, the number of patients required
3.6 Irradiation of the Chest Area 10 to estimate the risk of an expected small/very
4 Conclusions 12 small increase in RICs, occurring many years
after exposure to MDRT to a confined radiation
5 Guidelines for Clinicians 12
field, is large, yet (with a few exceptions) the
References 13 numbers treated for these specific indications are
small. Consequently, there have been very few
directly relevant trials to identify the risk of a
RIC following MDRT. Indeed, due to the long
latency time (LT) required, most of the studies
J. L. Nakamura (*) · S. E. Braunstein
Department of Radiation Oncology, discussed in this chapter relate to patients treated
University of California San Francisco, >30 years ago when RT treatment protocols were
San Francisco, CA, USA less sophisticated. The use of modern technology
e-mail: Jean.Nakamura@ucsf.edu;
also modifies the extent and location of normal
Steve.Braunstein@ucsf.edu
tissue exposure to ionizing radiation during RT
S. R. McKeown
(Lee et al. 2014; Liu et al. 2016). For example,
Biomedical Sciences Research Institute,
Ulster University, Coleraine, Northern Ireland, UK the use of intensity-modulated RT (IMRT) to
e-mail: sr.mckeown@ulster.ac.uk improve conformality may expose additional
Med Radiol Radiat Oncol (2022) 1

https://doi.org/10.1007/174_2022_349, © The Author(s), under exclusive license to Springer Nature Switzerland AG
Published Online: 29 September 2022
2 J. L. Nakamura et al.
healthy tissue to low doses of radiation because et al. 2020). The identification of genetic risk fac-
of the increased number of angles used. This adds tors is multifaceted and further validation is
another layer of complexity to the assessment of needed. In the future these approaches may allow
RIC risk for current treatment approaches when identification of risk mediators for the develop-
comparing to data from historical cohorts ment of RIC.
(Mazonakis and Damilakis 2017). The aim of this chapter is to present the evi-
It is thought that individual radiosensitivity dence that is currently available to assist clini-
may have a role in affecting the risk of a RIC in cians to make a judgement as to the benefits of
normal tissue exposed to ionizing radiation. MDRT protocols, balanced against the risk of a
However, even in patients exposed to high-dose subsequent RIC as it pertains to the individual
RT (HDRT) required for cancer treatments this circumstances of their patient.
has been very difficult to evaluate. In a recent
consensus review of genetic testing to identify
radiosensitivity profiles prior to HDRT, it was 2 Evidence Used in Estimation
agreed that unless patients have a recognized of the Excess Risk of RIC
radiosensitivity syndrome (e.g., ataxia- Following MDRT
telangiectasia) or a recognized germline muta-
tion, such as those involving the p53 (Braunstein This chapter updates previous reviews
and Nakamura 2013; Sherborne et al. 2017) or (Braunstein and Nakamura 2013; McKeown
Rb genes (Kleinerman et al. 2019), the influence et al. 2015; Mazonakis and Damilakis 2017) and
of genes on the radiosensitivity of normal tissues evaluates the currently available evidence of the
in most patients was not currently a cause for likelihood of a SMN developing as a result of
concern; however, they advised that further eval- exposure to radiation at doses pertinent to
uations should occur now that modern profiling MDRT. In fact, there are only a very limited num-
methodologies are available (Bergom et al. ber of directly relevant studies that have evalu-
2019). Several recent studies suggest that this ated the risks of RIC in patients with benign
may soon be possible. For example, when geno- disease especially when treated using modern
typic and proteomic data were integrated, a group techniques. To some extent doses and treatment
of eight plasma proteins combined with a VEGFA protocols in historical cohorts are similar but, in
gene variant were found to predict for radiosensi- many situations, there are key differences, adding
tivity (Drobin et al. 2020). In patients treated to the uncertainty of risk estimates for current
with RT to the chest area for Hodgkin’s lym- protocols. In addition, many of the previous stud-
phoma (HL) several single-nucleotide polymor- ies have limitations, e.g., there is marked vari-
phisms (SNPs) were associated with a higher risk ance in estimates of the received dose, dose
of radiation-induced breast cancer (BCa) (Opstal- exposure between individuals, age on irradiation,
van Winden et al. 2019). Genetic analysis may be and age at follow-up and often cohorts are small.
particularly pertinent for children treated with Directly relevant information has come from the-
ionizing radiation (Sherborne et al. 2017). A oretical models, phantom studies, and a limited
recent study of the Childhood Cancer Survivor number of clinical investigations, in which
Study (CCSS) cohort has shown that survivors MDRT has been used for the treatment of specific
with neurofibromatosis-1 (NF1) have a 2.4-fold benign diseases. However, most of the latter pro-
higher risk of a second malignant neoplasm tocols are no longer in use and involved treatment
(SMN) (95% CI, 1.3–4.3; p = 0.005); in one with antiquated equipment. Less direct evidence
cohort, treatment with RT but not alkylating can also be obtained by analyzing cohorts
agents further increased this risk (Bhatia et al. exposed to low-dose environmental or medical
2019). Recently a germline MUTYH mutation in radiation and for those treated with HDRT for
a pediatric cancer survivor has been implicated in cancer. The use of these information sources
the subsequent development of a SMN (Lavergne requires extrapolation up or down, which has
Estimating the Risk of Radiation-Induced Malignancy Following Radiotherapy for Benign Disease 3
inherent flaws. In addition, these risk assessments In a more recent phantom study, using similar
have also been informed using data based on a methodology, the lifetime attributable risk (LAR)
range of methodologies that are subject to several of a RIC following treatment with MDRT for ver-
important variables. tebral hemangioma was compared to the lifetime
intrinsic risk (LIR) in nonirradiated individuals
(Mazonakis et al. 2016). The authors calculated
2.1 Mathematical Modeling the radiation exposure of a range of organs (both
and Phantom Studies out-of-field and partially in-field) at risk follow-
ing exposure to MDRT (34 Gy) to four different
It is possible to use mathematical modeling and sites along the spine. The LAR for cancer devel-
phantom studies to provide more directly appli- opment in organs excluded from the irradiated
cable evidence since they have been specifically area was calculated to be trivial and considerably
designed to address the dose range pertinent to less than the LIRs. Although the risk was higher
MDRT. However, mathematical models require a in organs that were partially irradiated during
series of assumptions for which there may not be “treatment,” the risk was still very low and less
a consensus. In a recent review it was noted that than the LIRs for the same organs. It should be
many of the studies using radiobiology models in recognized that phantom studies require several
regular clinical use are abstract and empirical, assumptions making interpretation less certain,
and do not provide significant scope for mecha- as highlighted in a recent review (Mazonakis and
nistic interpretations (McMahon and Prise 2019). Damilakis 2017).
Few relevant phantom studies have been
described. However, a useful study of both male
and female anthropomorphic phantoms has 2.2 Epidemiological Studies
investigated the long-term risks of RIC in patients
treated with relatively modern RT protocols for a Epidemiological studies of cohorts exposed to
range of benign diseases (heterotopic ossifica- low-dose radiation (<5 Gy and in most situations
tion, arthritis of the shoulder or knee joints, heel in the mGy range), which is caused by environ-
spurs, and hidradenitis suppurativa) (Jansen et al. mental, occupational, or medical irradiation, also
2005). They calculated the risk of RIC using the provide an indication of RIC risk. However, the
International Commission on Radiological dose range is lower than that used for most treat-
Protection (ICRP) recommendation, which esti- ments used for benign disease and, for some
mates the average carcinogenic risk resulting cohorts, exposure is whole body and in some the
from ionizing radiation exposure to be 10%/Sv dose estimates are ill-defined. In contrast, the
for high dose and high dose rate exposure (ICRP numbers affected are often large improving reli-
1991a). The authors discussed in some detail the ability of the estimates. The largest group, which
basis of the assumptions which indicated that has been continuously monitored for >60 years,
when using MDRT to treat these conditions the are the survivors of the atomic bombings in
effective dose range was 5–400 mSv, providing a Japan; updates of the Lifespan Study (LSS) have
prediction of an increase in RICs of 0.5–40 per been published regularly. These data show that
1000 patients treated. They acknowledged that the incidence of most solid tumors has an approx-
this is a wide range, with age at exposure being a imately linear increase in relation to exposed
key risk modifier; body size and site of irradia- dose after a LT of about 10 years (Grant et al.
tion also influenced the risk. Consequently, it was 2017). Not unsurprisingly, a big difference in risk
advised that careful body positioning and shield- is found depending on the age at exposure, with a
ing should be employed to optimize target vol- tenfold difference between children and adults; in
ume coverage and reduce the effective dose to utero exposure has a similar level of risk to those
normal tissues to minimize the risk of a subse- exposed in infancy (Preston et al. 2008; Ozasa
quent RIC. et al. 2019). The incidence of RIC has been
quoted to decrease from about 15% per Sv of uni- define the dose limits for HDRT exposure of spe-
form whole-body irradiation for children cific organs (Hall and Giaccia 2018). It is now
<10 years to about 1% per Sv for adults exposed well accepted that cancer survivors have a higher
at >60 years (Kumar 2012). The data on hemato- risk of SMNs. Although this risk is small, it is
logical malignancies resulting from exposure to accepted for patients with cancer due to the
LDR are more varied, and the effects occur ear- greater threat from poor control of their present-
lier (discussed further below). A recent report on ing pathology. However, as cancer treatments
women exposed to long-term low-dose environ- become more successful there are an increasing
mental radiation (mean ~0.01 Gy) caused by con- number of cancer survivors who are at greater
tamination from the Chernobyl accident has also risk of the development of a SMN. Studies of
shown a small, but significant, increased risk of these patients can inform as to the risk of RIC,
BCa in those exposed to higher doses (Rivkind albeit the data is from differing protocols and
et al. 2020). consequent on higher dose exposures (Kumar
Recently studies have been published on two 2012; Braunstein and Nakamura 2013; Kamran
large groups of medical professionals exposed to et al. 2016; Schaapveld et al. 2015; Donin et al.
very-low-dose ionizing radiation during their 2016).
careers. One study of radiologic technologists A meta-analysis of >640,000 cancer patients
(n > 146,000; >72% female), who had worked for identified from the “Surveillance, Epidemiology,
at least 2 years between 1926 and 1982 in the and End Results” registries (SEER) in the USA
USA, has shown an increased risk of BCa (Doody has shown that, within 15 years of HDRT, there
et al. 2006; Preston et al. 2016). Further analysis are 5 excess cancers per 1000 individuals; these
of the incidence of self-reported cancers and can- data were acquired from 15 solid tumor types
cer mortality showed an approximately twofold (Berrington de Gonzalez et al. 2011). In a further
increased risk of brain cancer mortality and mod- systematic review of 28 eligible studies, they
est elevations in the incidence but not mortality identified 3434 patients who developed second
of melanoma and BCa. No other outcome evalu- cancers in 11 different organs known to receive
ated showed significant excess incidence or mor- >5 Gy. Most of the studies confirmed linear dose-
tality although some caution was advised in the response curves even up to ≥60 Gy; the main
interpretation of this data (Rajaraman et al. 2016). exception was thyroid cancer, which showed a
An increased risk of BCa has also been found in downturn above 20 Gy. They also confirmed that
a large cohort of medical workers in South Korea the risk varied according to the tissue of origin of
(>94,000). However, the radiation-related risks the second cancer (Berrington de Gonzalez et al.
identified were small and varied widely by sex 2013).
and occupational group, but they were most sig- Often several tissues, with different risks of
nificant for female radiologic technologists (Lee developing a RIC, are exposed to radiation during
et al. 2018). Overall, these low-dose groups show RT. In a study of HDRT for cervical cancer
that radiation exposure dose increases the inci- (n = 104,760) an increased risk for all second
dence of RIC though the numbers affected are cancers was found that was particularly evident
small and the LTs long. at heavily irradiated sites (colon, rectum/anus,
urinary bladder, ovary, and genital sites) as com-
pared to women in the general population. This
2.3 Second Malignant Neoplasms persisted beyond 40 years of follow-up and was
in Patients Exposed to HDRT modified by age at treatment (Chaturvedi et al.
for Cancer 2007). In a study of prostate cancer treatments,
men receiving HDRT (n > 50,000) showed that
The many sequelae of normal tissue exposure to most SMNs occurred in organs close to the treat-
HDRT during treatment of malignant tumors ment field, e.g., bladder and rectum; however,
have been well documented and indeed they 30% were induced in the lung which would have
only received a scatter dose of about 0.6 Gy. MDRT have very different normal tissue expo-
Overall, there was a small but significant increase sure profiles and this should be factored in when
in risk of a RIC (6%), as compared to those considering the potential for a subsequent RIC. In
treated by prostatectomy (n > 70,000) and the the following sections, several key “at-risk” tis-
relative risk (RR) increased in longer term survi- sue types are considered in relation to some of
vors (Brenner et al. 2000). the evidence available. However, none of the evi-
HDRT in childhood carries the greatest risk of dence is directly applicable since it comes from
a subsequent RIC since survival times are likely studies of HDRT and low-dose exposures. With
to be considerably longer and children are known this caveat, these studies can be used to estimate
to have an increased radiosensitivity (UNSCEAR the risks of MDRT treatment for individual
2013; Kutanzi et al. 2016). Consequently, current patients with specific benign diseases. Age is a
childhood cancer treatment protocols incorporate particularly important risk modifier and should
a specific aim to minimize the risk of RIC, by be factored in for all younger individuals. A
avoiding radiotherapy when possible, or alterna- selection of the more relevant studies was sum-
tively minimizing dose (Kutanzi et al. 2016; marized previously (McKeown et al. 2015) and
Turcotte et al. 2018). However, since some child- the discussion below now includes some of the
hood cancers involve an underlying germline more recent evidence.
mutation, this may also contribute to the observed
increase in the susceptibility to second malignan-
cies (Zhang et al. 2015; Sherborne et al. 2017). 3.1 Skin Cancer
The small size of pediatric patients further
increases risk, since scatter radiation will affect Skin cancer is a potential risk for all patients
more tissues (Hall 2006). receiving RT since there is, of necessity, almost
Since most of the evidence confirms an always a concomitant skin exposure, with a LT
approximately linear risk of RIC in relation to normally >10 years. A small but quantifiable
dose, the data obtained from cancer patients increase in non-melanoma skin cancer (NMSC)
treated with HDRT can be used to give some has been found following occupational expo-
guidance as to the expected lesser risks of RIC sure to ionizing radiation (Wang et al. 2002;
after exposure to MDRT. However, treatment Azizova et al. 2021) and RT for a range of
protocols/fractionation regimens will often be benign indications, using relatively low doses
different so any extrapolation from HDRT must (up to ~6 Gy but varying widely), e.g., tinea
be interpreted with caution. capitis (Shore et al. 1984; Ron et al. 1991;
Boaventura et al. 2012), acne, and other skin
disorders (Lindelöf and Eklund 1986; Karagas
3 Tissues at Risk of RIC et al. 1996). Most of these indications have not
Following MDRT for Benign been treated with MDRT for many years. There
Disease is now considerable evidence that the risk of
skin cancer is raised following many different
As discussed in the remaining chapters of this radiation exposure scenarios, with BCCs being
book, MDRT can be used to treat a wide variety the predominant tumor type found (Li and Athar
of benign diseases. Treatments involve many dis- 2016). In the LSS cohort BCC showed a signifi-
parate parts of the body, a variety of RT proto- cant excess relative risk (ERR) of 15, 5.7, 1.3,
cols, and patients of all ages. Currently, most and 0.9 that depended on age at exposure (0–9,
MDRT is used to treat older adults (aged >50), 10–19, 20–39, >40 years, respectively); this risk
though for some conditions children and younger increased 11% with each 1-year decrease in age
individuals might also be considered; in this lat- at exposure. No significant dose responses were
ter group the risk of a RIC, although small, will found for malignant melanoma or other skin
be higher. Individual indications treated with cancers (Sugiyama et al. 2014).
Modern HDRT protocols have resulted in lon- 2019). In the LSS cohort a linear dose-depen-
ger survival times in individuals treated for child- dent increase in the risk of RIC in the brain up
hood cancers. Consequently, a small but to 2 Gy was found, which was inversely related
significant increase in NMSC has now become to the age of exposure (Preston et al. 2007). In
apparent in the CCSS cohort, which is likely to a recent analysis, the risk of brain cancer was
be associated with their exposure to RT and/or found to be greater following childhood CT
linked to a genetic predisposition (Armstrong scanning compared to that obtained in the LSS
et al. 2011). Later analysis has shown not only an cohort; however, several likely confounding
increased incidence of BCCs (Watt et al. 2012) factors were identified showing how complex
but also an approximate 2.5-fold increase in the these assessments are (Smoll et al. 2016). In a
risk of melanoma (Pappo et al. 2013). recent meta-analysis of 6166 cases of meningi-
Studies of adults with benign conditions oma, an increased risk was associated with
exposed to above background radiation, such as repeated dental X-rays (pooled RR = 1.53 [CI
tuberculosis patients exposed to multiple fluoros- 1.26–1.85]) although not for occasional expo-
copies (average 77) during treatment, have shown sure; no increase was found for gliomas
no marked increase in skin cancer risk (Davis (Memon et al. 2019).
et al. 1989). The extent of sun exposure was also One well-recognized, if infrequent, outcome
thought to act synergistically with IR to cause of exposure to MDRT or HDRT is the occurrence
skin damage (ICPR 1991b; Shore et al. 2002); of meningiomas (Baldi et al. 2018; Chowdhary
however, more recent studies have resulted in et al. 2012; Godlewski et al. 2012). In a meta-
conflicting conclusions and the issue of interac- analysis of 66 studies of RT for a wide range of
tion of effects in the low dose range is considered conditions (mostly tumors) 143 patients were
to be unresolved (ICRP 2015). In the dose range found to have developed meningiomas attribut-
pertinent to some MDRT protocols there is more able to the RT (median age at RT was 12). The
likely to be a synergistic effect. It should be noted meningiomas presented at a younger age (80% at
that the lifetime risk of a radiation-induced BCC, <22 years) compared to spontaneous tumors
based on 100 cm2 skin treated to a mean dose of which have an incidence peak at age 50–70 years.
3 Gy, has been estimated to be ~0.006%, which is Atypical or malignant meningiomas were more
very much smaller than the spontaneous lifetime prevalent in the individuals treated with RT as
risk of >20% (Trott and Kamprad 2006). Overall, compared to the spontaneous meningioma
the data show a dose-dependent increase in the cohort. The median LT following RT was
risk of NMSC, mostly BCCs that can, for the 19 years, which was slightly shorter in males
most part, be treated successfully, although it has (18 years) versus females (24.7 years). LTs var-
been suggested that BCCs resulting from IR ied with a number of other factors including a
exposure are more aggressive and should ideally shorter LT in patients treated for leukemia com-
be excised with wider margins (Hassanpour et al. pared to benign conditions (14.9 versus
2006). Long-term surveillance and reporting of 32.1 years); though not proven, they indicated
suspicious changes in irradiated skin are advised, that this shorter LT might have been influenced
especially in individuals treated with RT as by adjunct chemotherapy. Patients receiving
children. HDRT had intermediate LTs (20.2 and 18.5 years)
whereas those exposed to the lowest doses, e.g.,
for tinea capitis, had the longest LTs. Patients
3.2 Brain Cancer exposed to partial brain RT as compared to cra-
niospinal or cranial RT had longer LTs, confirm-
Exposure to radiation is a well-substantiated ing that the larger the exposed volume the greater
risk factor for cancers in the brain/central ner- the risk of earlier development of a RIC (Paulino
vous system (CNS) with the evidence coming et al. 2009). However, for children receiving RT
from a range of different studies (Ostrom et al. to the head the risk of RIC is significantly higher
than background especially when treated at age patient 6 years after the treatment for arteriove-
<5 years (Neglia et al. 2006). nous malformation (Xhumari et al. 2015). Since
In a cohort of 10,834 children treated for tinea SRS is a relatively new modality, study follow-up
capitis with low-dose RT (mean 1.5 Gy), there periods are predominantly <15 years; therefore
were 73 neural tumors, an effect that was dose none can definitively prove the safety of SRS
related and which gave an overall RR of 6.9 (95% over a lifetime, though for older patients the data
CI: 4.1–11.6) for the development of a RIC of the shows that the risk is negligible. However, the
brain (Ron et al. 1988). A systematic review of 18 potential risk of a RIC should still be considered
studies investigating the risk of RIC following when treating younger individuals with SRS for
RT for childhood cancer confirmed the enhanced benign disease in the head and neck area.
risk for this cohort (Bowers et al. 2013). One The radiation dose to the orbit and surround-
recent reanalysis of a Portuguese cohort treated ing brain tissue during RT for eye conditions is
for tinea capitis underlines the persistence of this often in the order of 20 Gy. Based on several
risk. These individuals were followed up until approximations, the risk of a RIC in the brain due
2012 following relatively low MDRT (≥630 R) to ionizing radiation exposure has been estimated
in childhood during the period 1950–1956. to be ~0.2% above that expected (Trott and
Cancer cases were identified in 399 of the 3357 Kamprad 2006). Overall, there is now consider-
individuals, 49% higher than the age- and sex- able evidence that there is a small increase in
matched controls (standardized incidence ratios brain/CNS tumors following an initial radiation
(SIR) = 1.49; 95% CI: 1.35–1.64). The risk was exposure with most of the definitive data coming
slightly higher in males than in females and from cohorts exposed as children (Braganza et al.
slightly higher in the individuals exposed to a 2012). This effect also shows a clear age depen-
higher radiation dose (analyzed in two cohorts: dence, again highlighting that the use of RT in
325–475 R; ≥630 R). There were significantly children and young adults should always be con-
raised SIRs for thyroid and head and neck cancer; sidered carefully and radiation exposures should
an increased risk was also found for some can- be kept to a minimum whenever possible.
cers located far from the irradiated area (Antunes
et al. 2020).
During intracranial stereotactic radiosurgery 3.3 Thyroid Cancer
(SRS) the brain is exposed to high radiation doses
per fraction, albeit to very small volumes. Most Modern RT protocols for treating benign disease
follow-up studies have shown no or minimal rarely expose the thyroid to significant dose of
increase in brain tumors (Hasegawa et al. 2013; IR. However, previously several benign diseases
Wolf et al. 2019; Sherry et al. 2020). In a recent were treated with RT that resulted in significant
analysis of over 14,000 cases the overall inci- exposure of the thyroid with increased levels of
dence of SRS-associated malignancy was found thyroid cancer found in children treated for
to be 6.87 per 100,000 patient-years (95% CI benign diseases such as tinea capitis, cervical
1.73–18.50) and the cumulative incidence of adenopathy, and tonsillitis (Ron et al. 1995;
developing either a new or a transformation of a Sadetzki et al. 2006). Follow-up of these cohorts
benign tumor was 0.045% (95% CI 0.00–0.34) has led to identification of the lifetime risk of a
over 10 years. When compared to the risk of the RIC in the thyroid for children exposed before
development of a spontaneous primary CNS the age of 10 years to be ~1%/Gy, though in very
tumor, as measured in an age-adjusted normal young children this may be higher (Sadetzki et al.
population, there was no appreciable difference 2006; Trott and Kamprad 2006).
(Wolf et al. 2019). Although this large study In a systematic review of four studies
found no examples of malignancy in patients (n = 16,757) a significant increase in thyroid can-
treated for non-tumor-related disorders, one case cer was found in individuals receiving RT for a
study has reported a grade IV glioblastoma in a wide range of primary childhood cancers. In total
187 RICs were identified; a linear dose response shown an increase in leukemia in children even
was identified up to 10 Gy, which then plateaued when they are exposed to very low dose
about 30 Gy and reduced at higher doses. The (<100 mSv) (Little et al. 2018). In the LSS cohort
study also confirmed that the ERR/Gy increased a nonlinear dose response for most leukemias has
significantly with decreasing age of exposure been found, with the effects very dependent on
(p < 0.01) (Veiga et al. 2012). A meta-analysis of the time and age at exposure and leukemia type;
cancer in individuals exposed to ionizing radia- the nonlinearity is particularly associated with
tion associated with a range of diagnostic proce- acute myeloid leukemia (AML) (Hsu et al. 2013).
dures has confirmed a significant increase in Non-Hodgkin’s lymphoma (NHL) among men,
thyroid cancer risk (OR = 1.52 (CI 1.13–2.04)) although not in women, showed a weak link, and
(Han and Kim 2018). In a similar review, con- there was no evidence of an excess risk for either
fined to the risk from dental X-rays, analysis of HL or multiple myeloma (Hsu et al. 2013).
seven studies, including 78,546 individuals, Chronic myelocytic leukemia has the shortest LT
exposure (ever vs. never) was significantly asso- compared to other leukemias (mean ~5 years)
ciated with an increased risk of thyroid cancer (Little et al. 2013; Hsu et al. 2013; Little et al.
(n = 1572; pooled RR of 1.48 (CI 1.04–2.11)). 1999). However, the evidence linking chronic
This was also found for multiple exposures lymphocytic leukemia or adult T-cell leukemia to
(pooled RR of 1.87 (CI 1.11–3.15)) (Memon ionizing radiation exposure is equivocal; a recent
et al. 2019). These authors highlighted that the review has suggested that this may be influenced
doses to the thyroid have decreased markedly by the types of studies carried out (Bispo et al.
from an average of 390 mGy in the 1930s to an 2020).
average of 0.31 mGy at present (Chang et al. Similar outcomes have been found in individ-
2017) and present-day modern dental radiogra- uals treated for a number of benign diseases,
phy (without the use of thyroid shield) results in though these protocols are no longer in use—e.g.,
thyroid doses of a few hundredths of mGy to a ankylosing spondylitis (Brown and Doll 1965;
few tenths of mGy. Clearly, even at these low Darby et al. 1987), benign gynecological disor-
dose ranges an effect, though small, can be iden- ders (Sakata et al. 2012; Inskip et al. 1993), and
tified; in the MDRT range it will be somewhat peptic ulcers (Little et al. 2013). Recently a large
greater especially if the MDRT is in the proxim- study of patients treated for primary HL, NHL,
ity of the head and neck. A recent study of over and plasma cell myeloma showed an increase in
three million individuals receiving CT scans treatment-related AML and myelodysplastic syn-
(effective doses ranging from 0.5 to 18 mSv) drome (MDS) which was associated with a total
identified an elevated risk of thyroid cancer body exposure to ionizing radiation (indicative
(OR = 2.55, 95% CI = 2.36–2.75) which was range 5–15 Gy) (Radivoyevitch et al. 2018).
stronger in women than in men (Shao et al. 2020). Analysis of the LSS data has shown that adults,
Clearly, age is again identified as an important exposed to 1 Gy whole-body irradiation, have an
risk modifier for thyroid cancer, which highlights increased lifetime risk of hematological malig-
the need to limit exposure to MDRT in children nancy of ~1%. For MDRT to a localized field and
and younger adults. a much-reduced bone marrow exposure, this
should be less. For example, in patients with
ankylosing spondylitis exposed to a mean bone
3.4 Hematological Malignancies marrow dose of 1 Gy the increase in leukemia
risk was calculated to be about 0.2% (Trott and
It is known that exposure to ionizing radiation Kamprad 2006).
can cause leukemia, with a shorter LT (normally A recent European study of persons surviving
>3 years) as compared to solid tumors with a for >5 years after treatment for childhood cancer
peak at 15 years but still evident after 55 years (n = 69,460) found that 115 developed a second
(Hsu et al. 2013). A recent meta-analysis has primary leukemia; compared to the general
population this was a fourfold increased risk thatfive excess cases; this has been estimated to give
persisted beyond 20 years. However, treatment a lifetime risk of <0.1% for osteosarcoma after
information was limited, so the proportion of this1 Gy exposure (Preston et al. 2003). When a cor-
risk attributable to RT is unclear and subject to a
rection was made for a typical small RT field of
further analysis (Allodji et al. 2019). Several 100 cm2 the increase in risk of sarcoma after
studies have shown a small increased risk of leu- MDRT was calculated to be <0.001% (Trott and
kemias and other cancers in individuals who had Kamprad 2006).
computed tomography (CT) scans in childhood A recent retrospective analysis of the SEER
(Pearce et al. 2012; Mathews et al. 2013). A laterdata between 1973 and 2013 identified 1,884,469
reanalysis by Pearce and colleagues, using more individuals treated as adults for cancer (mean age
complete clinical information, confirmed the 60) and meeting carefully considered inclusion
original findings but with a reduction in the ERR criteria, one of which was a LT of >24 months.
of leukemias and brain tumors, although the Only 359 (0.02%) were diagnosed with a second
increases were both still significant; this reiter-
sarcoma (mean follow-up 9.2 years) and 242
ates the need to search out as much of the clinical
(0.01%) fitted the criteria for a RIS. The majority
information as possible to help eliminate poten- of these (126) had received HDRT for breast can-
tial confounding factors (Berrington de Gonzalez cer; when this group was compared to the “all
et al. 2016). In a study of over three million indi-
combined non-BCa” cases (116) the RR of RIS
viduals exposed to CT there was a reported was found to be 1.21 (CI: 1.01–1.45, p < 0.03)
increase in leukemia (OR = 1.55, 95% CI = 1.42– (Snow et al. 2021). Although the numbers are
1.68) but not NHL. The risk of leukemia was small it is important to recognize the possibility
greater in women and all individuals who were of a RIS, especially in survivors of BCa treated
<45 years of age on exposure (Shao et al. 2020). with MDRT/HDRT since any subsequent RIS is
A recent report of a 10-year follow-up of adoles- known to be more difficult to treat (Sheth et al.
cents treated for HL has confirmed an increased 2012). In addition, if patients have received a
risk of SMNs. In a cohort of 1711 (median fol- combination of chemotherapy with RT on first
low-up 7.3 years), the 10-year cumulative inci- treatment, the LT to develop a RIS has been
dence of SMN was 1.3% (95% CI, 0.6–2.0). found to be shorter as compared to RT alone
SMNs included 3 patients with AML, 11 with (Zhang et al. 2017).
solid tumors, and 3 NHL. The cumulative inci- Children from the CCSS cohort have been
dence was higher among patients who received shown to have an elevated risk of RIS with a
RT (p = 0.037). The authors indicated that prob- median LT of 11.8 following RT; this risk was
ably all cases of secondary leukemia and MDS further increased by exposure to anthracyclines
were captured; longer follow-up is needed to and was more likely if the initial treatment was
determine the risk of solid tumors (Giulino-Roth for HL or a primary sarcoma (Henderson et al.
et al. 2021). 2012). A similar European study confirmed this
finding with an ERR of 1.77/Gy for RIS
(Schwartz et al. 2014). A recent review of RIS
3.5 Soft Tissue and Bone Cancer has highlighted several studies worldwide which
provide evidence for sarcoma as one of the more
It has been known for many years that radiation- common, although rare, SMNs in childhood can-
induced sarcoma (RIS) can occur following RT cer survivors; this was confirmed in their analysis
for a range of malignant and nonmalignant dis- of the SEER databases. Of note was the relatively
eases but at very low frequency, and with consid- short LT for childhood cancer survivors (means
erable uncertainty if the dose is <10 Gy (Kim ranging from 4.1 to 15.5 years for different pri-
et al. 1978; Berrington de Gonzalez et al. 2012). mary tumor types) confirming that individuals
Studies of the LSS cohort, who had an estimated exposed to RT as children need careful follow-up
mean total-body dose exposure of 0.23 Gy, found (Nguyen et al. 2020). A previous study in ten
centers located in four Asian countries also con- eate those individuals who harbor susceptibility
firmed a small number (n = 44) of patients with to radiation-induced carcinogenesis; additional
identified RIS, who generally had a poor progno- studies will be needed to validate this risk assess-
sis for treatments for the RIS; however, the over- ment strategy.
all incidence was not provided (Joo et al. 2018). Overall RIS is recognized as a rare but identi-
A recent study of patients treated with HDRT for fiable risk following HDRT, especially when
nasopharyngeal cancer (n = 14,074) has reported exposure occurs at a young age. MDRT to a con-
a low, but significant, incidence of RIS (0.16%; fined field and to older patients should reduce this
22 cases) with a median LT of 8.5 years (range small risk still further, although it cannot be
3–36); these patients were more difficult to treat excluded completely. For younger patients,
successfully with a median survival time of genetic analysis of the primary tumor could aid in
34 months and a 5-year overall survival of 14.4% identifying patients of higher risk of a SMN.
(Lou et al. 2021).
Recent studies have shown that genetic
defects can affect the incidence of RIS. For 3.6 Irradiation of the Chest Area
example, patients with an inherited defect in the
retinoblastoma gene have a slightly increased Previously RT was used in women (mostly aged
risk of RIS (Gregersen et al. 2020) and tumors at between 20 and 40) to treat benign disease of the
other sites (Kleinerman et al. 2019). The latter breast, e.g., for acute mastitis. However, an
study showed that this can be further elevated by increased risk of a subsequent cancer was found
prior RT and chemotherapy, whereas the former (Shore et al. 1986; Mattsson et al. 1995). In a
study failed to show any additive RT-induced review of three eligible studies evidence has
effect for patients with RIS. The risk of a RIS in shown that there is a linear increase in the excess
patients with inherited retinoblastoma was found risk of BCa following radiation exposure, as for
to persist for over 60 years (Kleinerman et al. other solid tumors (Berrington de Gonzalez et al.
2019). In addition, a recent study has implicated 2013). A study of Swedish women (n = 17,200),
TP53 mutations to a possible enhanced risk of who were exposed to low-dose RT (median dose,
RIS, and possibly other SMNs. Whole-exome 0.040, range: 0.010–0.120; maximum <5 Gy) for
sequencing was carried out in RISs excised from hemangioma as infants (<18 months), showed a
two survivors of pediatric cancer. Somatic TP53 dose-related increased risk of subsequent BCa
mutant variants were enriched in the transcrip- (Lundell et al. 1996). Reanalysis found 899 cases
tomes for both sarcomas; one survivor, who had of BCa, with an ERR at age 50 years of 0.48/Gy
no identified familial cancer predisposition, also (95% CI 0.28; 0.69) (Eidemüller et al. 2015); this
had a germline mutation. Analysis of TP53 cod- risk was further increased for women with a
ing exons in germline specimens was also car- familial history of BCa (Eidemüller et al. 2021).
ried out in 37 evaluable patients from the CCSS When modeling was used to analyze the data, a
survivor cohort who had subsequently developed significantly better fit was found when a path for
a SMN; ten (27%) were found to have a germline genetic instability (initiated by radiation
TP53 variant with no identified family history. exposure) was included; this implies that early
This suggests that detection of, probably sponta- induction of genetic instability may increase the
neous, germline TP53 variants at the time of pri- risk of RIC, though this model needs confirma-
mary cancer diagnosis could help to identify tion (Eidemüller et al. 2015). These results high-
patients at higher risk for SMN development; light the need to keep, as low as is possible,
this subset could then benefit from modified radiation exposure to the chest wall/breast espe-
therapeutic strategies and/or intensive posttreat- cially for young girls.
ment monitoring (Sherborne et al. 2017). As For many years it has been recognized that
germline sequencing becomes increasingly survivors who have been treated when young
available, this and similar approaches may delin- with RT to the chest for HL have a 5–20 times
increased risk of BCa (Swerdlow et al. 2012; In a modeling study of the risk of RIC follow-
Schaapveld et al. 2015; Giulino-Roth et al. 2021), ing intermediate-dose RT (20–35 Gy) for medi-
a risk that can be partially ameliorated using dose astinal HL, a marked reduction in the risk of
and field reduction protocols, when appropriate subsequent BCa and lung cancer was calculated
(de Bruin et al. 2009). It has also been recognized when involved field RT was compared to mantle/
that this risk can be reduced by adjuvant chemo- extended-field RT. This study demonstrated that
therapy, probably through initiation of early care in reducing the field size to a minimum, use
menopause (Travis et al. 2003; van Leeuwen of modern RT techniques, and dose reduction
et al. 2003), an effect confirmed more recently, (where justified) will significantly reduce the
though the risk of gastrointestinal cancer was subsequent risk of a RIC (Hodgson et al. 2007).
found to be increased (Schaapveld et al. 2015). A A cautious estimate of the increased lifetime risk
study of 1230 women from the CCSS cohort, of BCa for a breast exposed to 1 Gy has been
treated as children with RT to the chest area, has made for different age groups: ~5% (<35 years),
shown that lower dose RT (median, 14 Gy; range, <3% (35–45 years), and much less, or possibly
2–20 Gy) to a large volume (whole-lung field) zero above 45 years (Trott and Kamprad 2006).
had a similarly high risk of BCa as survivors As was discussed previously, there is evidence
treated with higher doses (median, 40 Gy) to the that lung cancer incidence shows a small, but
mantle (extended) field. The cumulative inci- quantifiable, increase following RT to the chest
dence of BCa by age 50 years was 30% with a area (McKeown et al. 2015). The absolute risk of
35% incidence among HL survivors; BCa- a RIC has been estimated to be ~1% within
associated mortality at 5 and 10 years was also 25 years of a 1 Gy exposure to the lung (Trott and
substantial (12% and 19%, respectively) Kamprad 2006). In a study of lung cancer in
(Moskowitz et al. 2014). In a recent update, mor- patients treated for HL there was clear evidence
tality after a BCa diagnosis was found to be of a dose-dependent increase in risk up to at least
higher in CCSS survivors than in women with de 30 Gy (Gilbert et al. 2003; Travis et al. 2002).
novo BCa (Moskowitz et al. 2019). These and This effect showed an additive increase with
other studies reflect the burden of comorbidity in adjuvant chemotherapy and a multiplicative
this cohort and highlight the need for risk reduc- effect of smoking. Recently the risk has been
tion interventions whenever possible (Kamran confirmed to be present for over 40 years; when
et al. 2016). compared to the general population, the SIR for
Analysis of patients (n = 3905) treated for HL lung cancer was 5.2 for patients treated for HL at
showed an overall excess risk of an SMN of age 35–50 years (Schaapveld et al. 2015).
20.9% for all patients with BCa accounting for Evidence from this study and the LSS cohort also
40.5% of the excess risk of any second cancer in confirmed that smoking significantly increases
women. The cumulative incidence of second the excess risk of lung cancer compared to non-
solid cancers did not differ according to the study smoking survivors (Furukawa et al. 2010).
period (1965–1976, 1977–1988, or 1989–2000) A dose-related increase in RIC in the abdomi-
indicating that treatment changes during this nal area has also been reported in individuals irra-
period had not affected the rate of SMNs diated for peptic ulcers (mean dose 14.8 Gy),
(Schaapveld et al. 2015). Another approach to though this treatment is no longer in use (Carr
reduce BCa-associated mortality, in women et al. 2002). In a reanalysis of this cohort there was
exposed as children to RT, may be to initiate confirmation of a statistically significant (p < 0.05)
early annual breast screening (at ages 25–30) excess risk for most cancers including lung cancer.
using MRI, with or without mammography; a For all tumor types, age at exposure was inversely
recent modeling analysis of childhood cancer related to RR (Little et al. 2013). More recently a
survivors has found that this approach, despite study of the SEER database identified >2 million
the potential small additional radiation exposure, treated for cancer as adults (>18 years); the inci-
may reduce mortality by >50% (Yeh et al. 2020). dence of SMN in survivors was nearly 1 in 12, the
most common of which was lung cancer though a volume of red bone marrow exposed to radiation
direct link to treatment-related factors, including should be kept to a minimum to minimize the
RT, was not evaluated (Donin et al. 2016). A previ- slightly increased risk of leukemias which have
ous analysis of this database has shown that <10% shorter LTs. The risk of other solid tumors will
of the SMNs can be attributed to RT (Berrington also depend on the tissue within, or close to, the
de Gonzalez et al. 2011). radiation field and the volume exposed. The addi-
tional data published over the last 5 years, which
includes updates of previously identified cohorts,
4 Conclusions confirms the higher and enduring risk that chil-
dren and young adults have of developing a RIC
This review updates a previous review on the risk following exposure to ionizing radiation, an
of a RIC in patients subject to MDRT (McKeown effect which is even apparent at low diagnostic
et al. 2015). Since this time there have been few doses. Consequently, it is prudent to advise that
directly relevant studies published, although radiation exposure to younger individuals should
there are many recent indirectly relevant studies be used only when clinically justified and when
which confirm the previous conclusions. In a sys- other treatment/diagnostic options are not avail-
temic review of validated studies of RT for pri- able or are unsuitable.
marily cancer, across a range of protocols using
total doses >5 Gy, the risk of SMN showed a lin-
ear dose response up to above 60 Gy, except for 5 Guidelines for Clinicians
thyroid cancer which flattens out above ~20 Gy
(Berrington de Gonzalez et al. 2012). This pro- The preceding data summarizes extensive evi-
vides some assurance that the risk associated dence that RT is associated with a small risk of
with MDRT can be evaluated from the studies inducing malignancies, although the evidence is
discussed, allowing for (1) the lower/higher mostly from higher doses than those used for
doses (if applicable), (2) the tissues most at risk benign disease and in many cases using different
within the radiation field, and (3) the strong treatment protocols. Where does this leave the
inverse association with age at first exposure treating physician? Unlike more common
(Kamran et al. 2016). Where the patients are therapy-associated toxicities such as radiation-
young women the recently updated advice on induced pneumonitis, in which dosimetry and
surveillance should also be considered (Mulder volume-driven constraints guide planning, simi-
et al. 2020). As discussed, a variety of genetic lar dose constraints are not validated for RICs.
approaches are beginning to provide evidence Additionally, the epidemiologic data describing
that patients can be stratified for their risk of the incidence of RICs is based on older RT tech-
developing a RIC. In the future this should greatly niques that are challenging to extrapolate to mod-
help to inform treatment options and follow-up ern conformal RT practices. Modern molecular
surveillance protocols. analyses of RICs indicate that germline variants
Overall, for older adults treated with RT for play a pathogenetic role in RIC induction. As
benign disease, especially located in peripheral awareness of germline genetic variants increases,
tissues, the risk of a RIC is likely to be very small this information, when validated, may be included
and it reduces further with increasing age at treat- in RIC risk estimation for individual patients.
ment. For most adults it is reassuring to note that Evidence-supported considerations also include
the intrinsic risk in most situations is consider- patient age and anatomic site; the benefit of
ably greater than any risk from low-dose radia- MDRT for benign conditions should be weighed
tion and MDRT exposure. Although a RIC of the against the risk of RICs developing in younger
skin is possible, for most patients this risk is low patients, particularly pediatric patients, as well as
and the tumor types arising are likely to be treat- the volume and organs (for example chest irradia-
able (predominantly BCC). Where possible, the tion) exposed.
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Understanding Radiation Units
François De Blois
Contents The goal of this chapter is to compile radiological

1 SI Radiological Units 19 units that are or were used to quantify radiation-
related quantities or its effects in the context of
2 The Initial Radiological Units 21
medical treatments since the discovery of radia-
3 Historical Radiological Units 22 tion. All quantities that are measurable are called
References 25 physical quantities. A physical quantity is com-
posed of a numerical value (magnitude) and a
unit in which that quantity is measured. The
accuracy of radiation measurement is important
in reporting and reproducing treatments for
benign disease.
1 SI Radiological Units
The currently used metric system of units is

known as the Système International d’Unités
(International System of Units) with the interna-
tional abbreviation SI. This system was first
based on the basic units centimeter, gram, and
second (CGS) and subsequently on meter, kilo-
gram, and second (MKS) (Gyllenbok 2018). It
was then refined and is now composed of seven
basic physical quantities presented in Table 1
from which all other quantities and units are
derived. Some important derived units used for
radiological units are presented in Table 2.
The Système International obtains its interna-
tional authority from the Meter Convention that
F. De Blois (*) was endorsed in 1875 by 17 countries; the current
Department of Oncology, McGill University,
Montreal, QC, Canada membership stands at 63 member states and 38
e-mail: deblois.francois@gmail.com; associate states and economies (https://www.
francois.deblois@mcgill.ca bipm.org/en/home n.d.).

Published Online: 12 April 2023
20 F. De Blois
It is important to note that units are often P0 273.2 + T

paired with a prefix to simplify their writing. A results. Typically, KTP = · , where
P 273.2 + T0
summary of important prefixes is presented in P0 and T0 are, respectively, the reference pressure
Table 3. and reference temperature.
It is also important to understand that the mea- There are three categories of units that are
surement conditions may alter the magnitude of used to quantify radiation:
the measured quantity. For example, when mea- 1. Exposure-related units:
suring ionization in open air, the temperature and These units represent a quantity proportional to
pressure will change the density/mass of air in the ability of a radiation field to ionize air.
the volume of interest. Therefore, a correction Radiation passing through a gas liberates ion
(KTP) to normal temperature and pressure condi- pairs. If the gas is in an electric field, move-
tion (NTP) must be applied to obtain consistent ment of ion pairs can be measured as a cur-
rent, which is proportional to exposure rate.
2. Quantity of radioactive material-related
Table 1 Base SI units units:
Quantity name Unit name Unit symbol Generally expressed as the number of nuclear
Length Meter m transformations (or disintegrations) that occur
Mass Kilogram kg in a sample per unit time. The term for quan-
Time Second s
tity of radioactive material is activity.
Electric current Ampere A
3. Dosage-related units:
Temperature Kelvin K
Amount of substance Mole mol
These units represent quantities that are propor-
Luminous intensity Candela cd tional to a physical or biological effect
imparted to the irradiated material.
The SI units used to quantify the various
Table 2 SI derived units (used in the definition of radio- aspects of radiation are listed in Table 4 as well as
logical units) the conversion to their corresponding units in the
Quantity Unit Gaussian system (base units of centimeter-gram-
name name SI value Basic units second (CGS)) (Gyllenbok 2018).
Charge Coulomb C s·A In addition, any units can also be expressed as
Charge esu 3.33564 × 10−10C cm3/2·g1/2·s−1 a rate by simply dividing the unit by the unit of
Energy Joules J kg·m2/s2
time (· 1 ).
Energy Electron- eV 1.602 × 10−19 J s
volt There are three units in the SI that represent
Energy erg 10−7 J g·cm2/s2 dosage. The three quantities share the same basic
Frequency Hertz Hz s−1 unit (J/kg) but are expressed in the form of gray
or sievert:
1. Radiation Absorbed Dose (D): This is a
Table 3 List of prefixes
measure of the energy imparted to matter
when an ionizing radiation field interacts with
Prefix Abbreviation Value Prefix Abbreviation Value
matter. Absorbed dose is expressed as energy
deca da 101 deci d 10−1
hector h 102 centi c 10−2
(J) absorbed per unit mass (kg) of irradiated
kilo k 103 milli m 10−3 material.
mega M 106 micro μ 10−6 2. Radiation Equivalent Dose (H): This takes
giga G 109 nano n 10−9 into consideration the fact that different
tera T 1012 pico p 10−12 forms of ionizing radiation can produce dif-
peta P 1015 femto f 10−15 ferent biological effects for the same absorbed
exa E 1018 atto a 10−18 dose. The equivalent dose attempts to nor-
zetta Z 1021 zepto z 10−21 malize these differences. Equivalent dose is
yotta Y 1024 Yocto y 10−24 the product of the absorbed dose, and a modi-
Understanding Radiation Units 21
Table 4 SI radiation quantities and conversion to Gaussian units

Quantity name Unit name Category Old unit Conversion
Exposure (X) [C/kg] Exposure 1 esu 10 -4 C
(roentgen) 1 R = 1 R = 2.58 ´
cm 3 airSTP kgair
Activity (A) becquerel [1 Bq = 1 s−1] Quantity (curie) 1 Ci = 3.7 × 1010 s−1 1 Ci
1 Bq =
3.7 ´ 1010
Absorbed dose (D) gray [1 Gy = 1 J/kg] Dosage erg 1 Gy = 100 rad

(rad) 1 rad = 100
g
Equivalent dose (H) sievert [1 Sv = 1 J/kg] Dosage (rem) 1 rem = 1 rad 1 Sv = 100 rem
Effective dose (E) sievert [1 Sv = 1 J/kg] Dosage (rem) 1 rem = 1 rad 1 Sv = 100 rem
Table 5 Recommended radiation weighting factors ation of organs and tissues is nonuniform.
Identical E yields the same “radiation detri-
Radiation wR
Photons, electrons (all 1
ment” as a numerically equivalent whole-
energies) body dose. wT values are assigned by the
Protons and charged pions 2 ICRP (1991, 2007).
Neutrons Vary with neutron
energy
Alpha particles 20
2 The Initial Radiological Units
fying factor called the radiation weighting
As soon as radiation was discovered at the end of
factor (wR), which reflects the relative bio-
the nineteenth century, it started being used for
logical effectiveness of the type of radiation.
medical purposes. Several approaches to describe
Therefore, the equivalent dose is defined as
the effects of radiation evolved into developing
H = D ∙ w R.
units to quantify the phenomenon, often with
Radiation weighting factors (wR): These are
limited understanding of the precise underlining
indices of the “relative biological effective-
physics.
ness” (RBE) of a radiation. RBE is a compli-
The seminal discoveries that led to the use of
cated function of the type of radiation,
radiation in medicine were:
energy, and biological system under consid-
1. The discovery of X-ray by Roentgen (also
eration. wR are not measured. They are deter-
spelled Röntgen) in (1895, 1896).
mined by the International Commission on
2. The discovery of radioactivity of uranium
Radiological Protection committee (ICRP
compounds by Becquerel (1886).
2007) and summarized by radiation type in
3. The discovery of polonium and radium by
Table 5.
Marie and Pierre Curie (1898a, b).
3. Radiation Effective Dose (E): This is
Two physical methods were rapidly recog-
intended to reflect the total biological effect
nized to measure X and gamma rays: photo-
of a given radiation exposure on a human. It
graphic and electrical. The photographic method
is a weighted average of the individual doses
depends upon the action of radiation with photo-
to several important tissues or organs of inter-
graphic plates and the electric method on the dis-
est (T) such that E = åH T ·wT , where wT are
T charge of electrification caused by radiation. The
the tissue weighting factors. The effective electrical method relies on the measurement of
dose is a derived quantity, not a measurable the conductivity acquired by air that would yield
quantity. It applies to situations where irradi- a fast and fairly accurate quantitative measure-
22 F. De Blois
ment allowing to compare different results. “Quantity of x-radiation which, when the second-
Roentgen himself, right after the discovery of ary electrons are fully utilized and the wall effect
X-rays, proposed to use these methods. However, of the chamber is avoided, produces in one cubic
it was in 1908 that a unit of “dose” was defined centimeter of atmospheric air at 0 °C and 76 cm
based on these principles by Villard as “that of mercury pressure, such a degree of conductiv-
quantity of x-radiation which liberates by ioniza- ity that one electrostatic unit of charge is mea-
tion one e.s.u. of electricity per cm3 of air under sured at saturation current” (International
normal conditions of barometer and temperature” Congress of Radiology International X-ray Unit
(Villard 1908). The Villard unit was slightly Committee 1928). The adoption of the r unit
modified in 1918 by Krönig and Friedrich who greatly simplified communicating and transfer-
renamed it e-unit. Behnken also modified it ring experience within the medical radiation
slightly in 1924 and named it R-unit. Moreover, community.
another R-unit also based on ionization measure- In parallel, several other units have been pro-
ments had been defined by Solomon in 1925. posed and used to quantify the effect of radiation.
This differed from the Behnken R-unit by more The next section of this chapter summarizes a
than a factor of 2. few of these units.
To clarify the approach and aim toward a con-
sistent definition of dose, a group of scientists
formed the “International X-ray Unit Committee” 3 Historical Radiological Units
at the second International Congress of Radiology
in Stockholm in 1928. They proposed using a Table 6 presents a collection of radiological units
new international unit of “dose” called the roent- indicating name, definition, category of radiation
gen, labeled with the symbol r (lower case to unit, who introduced it (when known), and
avoid confusion with the R units of Behnken and approximate year of introduction (when known)
Solomon). 1 r of dose was defined as the by alphabetical order.
Table 6 Historical radiological units

Unit namea Value/definition Category From Year
Behnken’s 1 Behnken’s unit = Villard unit (@ Exposure H. Behnken 1927
unit or R unit P0 = 760 mmHg; T0 = 18 °C)
D unit X-ray exposure that corresponds to 102 roentgen Exposure Mallet 1925
Dose area In units of Gy·cm2 Dosage
product Corresponds to the product of the air kerma in Gy
(DAP) and the exposed area in cm2. Used in radiology to
estimate the dose
E unit Unit of X-ray exposure rate. Corresponds to 1 Exposure W. Duane 1914
roentgen/s
e unit Unit of X-ray exposure. Corresponds to about 6–8 Exposure W. Friedrich 1916
roentgens (Kronig and Friedrick 1918)
eman Used to express the radon isotope 222Rn activity Quantity
concentration of water. 1 eman = 10−13 Ci/cm3 or
3.7 × 10−3 Bq/cm3
erg per gram The CGS unit for absorbed dose rate and kerma Dosage
second rate; 1 erg per gram second = 10−4 W/kg
(erg·(g·s))
fair (фэр) Corresponds to the dose of radiation received by a Dosage
unit mass of soft biological tissue, at which the
energy absorbed in the tissue corresponds to the
energy absorbed by air of the same mass, with an
exposure dose of 1 R. 1 fair = 85 erg/g (0.0085 J/kg)
Table 6 (continued)
Finsen unit Unit of erythemal flux density. Used to measure Exposure Niels Ryberg 1903
(FU) the intensity of ultraviolet radiation with respect to Finsen
Finxen unit its capacity to cause skin reddening. 1 FU
finse corresponds to an ultraviolet light (wavelength of
296.7 nm) of energy density 105 W/m2
French = 4/9·German units Exposure 1926
roentgen
German R 1 German R unit = 2.5·Solomon R units Exposure
unit
gram-rad Integral absorbed dose unit corresponding to Dosage ICR 1953
(g·rad) 10−5 J = 100 erg = 1000 rad = 10 Gy
gram- Energy absorbed by 1 g of air when receiving 1 Dosage
roentgen roentgen of radiation. Corresponds to 8.38 μJ
Hampson unit Unit of X-ray exposure corresponding to 1/4 of the Exposure Hampson
erythema dose
Holzknecht Unit of X-ray exposure corresponding to 1/5 of the Exposure G. Holzknecht
unit erythema dose
K factor Used to characterize a gamma (γ) emitter. The γ-ray Exposure
dose rate in roentgens per hour at a distance of
one centimeter from a one millicurie point source
of radiation
Kienbock’s Unit of X-ray exposure corresponding to 1/10 of the Exposure R. Kienbock
unit (X) erythema dose
Mache, Concentration of radioactivity. Defined as the Quantity International 1930
mache, or concentration of elemental radon gas per liter of Radium
mache unit water. 1 mache = 3.64 Eman Standard
(ME) 1 mache = 3.7 × 10−7 curie (Ci) (or 13,760) Committee
becquerel per milliliter (Arthur Klein 1988)
millicuries— Used to characterize the X-ray dose from radon Dosage
destroyed mainly (from France). It was defined as a dose
(mcd or equivalent to that emitted from a radioactive source
mc.d.) during the time its radioactivity falls by a millicurie
Minimal Refers to the reddening of skin from ultraviolet Dosage
erythema dose radiation. The reddening varies between each
(MED): also individual depending on their skin type. The MED is
called skin related to the time a person can be irradiated before
erythema dose his or her skin is burned. 1 SED per hour
(SED) corresponds to 27.778 mW/m2 of skin surface. 1
SED corresponds to a dose of 100 J/m2 of skin
surface
Parker Alternate name for the rep Dosage H.M. Parker 1950
pastille dose Dose of radiation required to change the color of a Exposure Early 1920s
or B-dose barium platinocyanide pastille from a specified
green color (Tint “A”) to a specified reddish color
(Tint “B”)
Corresponded to about 500 roentgens
Measured in a Sabouraud-Noire and Bordier
instrument (Hirsch 1920)
R units 1 R = 1 Solomon R unit·h/2100 Exposure
(continued)
24 F. De Blois
Table 6 (continued)
rad (radiation SI, CGS unit to measure absorbed radiation dose Dosage ICRU 1918–
absorbed First defined as the dose to kill a mouse in 1918 1953–
dose) Then defined by the ICRU as the amount of 1970–
radiation that leads to the absorption of 100 ergs of
energy per gram of a substance (0.01 J/kg) in 1953.
Hence, 1 roentgen of X-rays or gamma radiation in
water or soft tissue produces an absorbed dose of
1 rad = 1 μJ/kg
In 1970, the rad was defined in SI as the number of
ergs per hectogram. 1 rad = 10 mJ/kg
In 1975, the rad was replaced in SI by the gray (Gy).
1 rad equals 0.01 Gy
The symbol “rd” was sometimes used to avoid
confusion with radian
Radiation unit Corresponds to the becquerel unit Exposure
(ru)
rem (roentgen SI, CGS, and metric unit of equivalent dose, Dosage H.M. Parker/ 1944
equivalent effective dose, and committed dose. Used to ICRU
man) estimate potential health effects of ionizing radiation
on the human body. Corresponds to the quantity of
radiation that would produce the same biological
damage in a human being as would result from the
absorption of 1 rep of X-rays. To weight different
forms of radiation, a relative biological effectiveness
factor (RBE) was used. An RBE factor corresponds
to the ratio of the X-ray dose to the dose of another
type of radiation causing the same amount of
damage. 1 rem = 0.01 Sv
rep (roentgen Alternate name for the Parker. Absorbed dose unit Dosage H.M. Parker 1950
equivalent that changed definition with time. Defined as the
physical) amount of energy deposited in a material by X-ray
radiation producing 1 esu of charge (measured
experimentally). Initially estimated to be 83.8 erg/g
(8.38 mGy), it was later improved to 93 erg/g
(9.3 mGy) until more accurate measurements
concluded that 1 roentgen of air kerma yielded
8.77 mGy in dry air and 9.6 mGy in soft tissue
rhm Measures the strength of gamma rays. A 1 rhm Exposure
(roentgen- source ionizes at a rate of 1 roentgen per hour at a
hour-meter) 1 m distance
1 rhm = 1 roentgen/h @ 1 m
roentgen (R or Used to characterize the ionizing ability of Exposure ICR/BIPM 1937/1960
r) X-radiation or gamma rays. Defined by the 1937
Radiological Congress in Chicago as the amount of
X-radiation or gamma radiation that produces
ionization = 1 electrostatic unit of charge (esu),
either negative or positive, in 1 cm3 of dry air at
0 °C and at standard atmospheric pressure
(760 mmHg) (International Congress of Radiology
International X-ray Unit Committee 1928)
Redefined in the mid-1960s by the BIPM group
(https://www.bipm.org/en/home n.d.) as 2.58 μC/kg
of air
Table 6 (continued)
roentgen per Exposure rate = 2.58·10–4 C/(kg·s) Exposure
second
rutherford (Rd Unit of radioactivity corresponding to Quantity E. U. Condon 1946
or rd) 1 megabecquerel (MBq) or 1/37 millicurie & L.F. Curtiss
Solomon R Intensity of an X-ray beam that produces the same Exposure Solomon 1925
unit ionization as that from 1 g of radium placed 2 cm
from an ionization chamber when there is a
platinum screen of ½ mm thick between the source
and an ionization chamber (Solomon 1925)
strontium unit Used to measure the radioactive concentration of Quantity
or sunshine strontium-90 (Sr90). 1 SU is the activity of Sr90
unit (SU) absorbed per kilogram of calcium. 1 SU = 37 Bq/
kg
Surface Referred to as exposure area product. Determined by Exposure
integral integrating the exposure over the surface area in
exposure units of R-cm2
(SIE)
Villard unit Quantity of radiation which produces by ionization Exposure P. Villard 1908
1 esu of electricity per cubic centimeter of air
under NTP conditions
a
In general, full names of physical units are spelled out with initial letter in lower case even when they originate from
a surname (e.g., roentgen). However, when its name contains “unit,” the first name if coming from a surname starts with
a capital letter (e.g., Villard unit). Abbreviations for physical units that come from a surname are commonly spelled out
with a capital letter (e.g., R for roentgen)
ICRP (1991) 1990 recommendations of the International

References Commission on Radiological Protection. ICRP
Publication 60. Ann ICRP 21:1–3
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Bequerel H (1886) C R Hebd Seances Acad Sci. 122 International Commission on Radiological Protection.
pp 150–159, p 420, p 501, p 559, p 689, p 762, et ICRP Publication 103. Ann ICRP 37:2–4
p. 1086 – C.R.T. 123 p 855 International Congress of Radiology International X-ray
Curie M (1898a) Rayons émis par les composés de Unit Committee (1928) International X-ray unit of
l’uranium et du thorium. C R Hebd Seances Acad Sci intensity. Br J Radiol 1:363–364
126:1101–1103 Kronig B, Friedrick W (1918) Physikalische und biolo-
Curie M (1898b) Sur une substance nouvelle radioactive, gische Grundlagen der Strahlentherapie. Urban and
contenue dans la pechblende. C R Hebd Seances Acad Schwarzenberg, Berlin. (in German)
Sci 127:175–178 Roentgen WC (1895) Ueber eine neue Art von Strahlen.
Gyllenbok J (2018) Encyclopaedia of historical metrology, Sitzungsberichte der Physikalisch-Medizinischen
weights, and measures, vol 1, 1st edn. Springer, Cham Gesellschaft zu Wuerzburg 29:132–141
Hirsch IS (1920) The principles and practice of roent- Roentgen WC (1896) Science 3(59):227–231
genological technique. American X-Ray Pub. Co, Solomon I (1925) Uber die Wahl einer
New York Quantimetrischen Einheit. Strahlentherapie
https://www.bipm.org/en/home 20:642–650. (in German)
Villard P (1908) The radiosclerometer. Arch d’Élect Med
Bordeaux 14:692
Autoimmune Disorders
Andrew Martella, Yushen Qian,

and Rishabh Chaudhari
Contents 1 Graves’ Ophthalmopathy or

1 Graves’ Ophthalmopathy or Hyperthyroid
Hyperthyroid Ophthalmopathy 27 Ophthalmopathy
2 Hashimoto’s Thyroiditis 34
In select cases, external beam radiation to the
3 Immunosuppression 37
retrobulbar tissues and eye muscles produces
3.1 Local Field Irradiation in Renal
Transplantation 40 reduction of signs and symptoms associated
with autoimmune eye disease. Doses used com-
4 Lupus Erythematosus (Lupus Nephritis) 41
monly are 20 Gy in 10 fractions calculated to the
5 Multiple Sclerosis 42 midplane for bilateral cases. Soft tissue findings,
6 Myasthenia Gravis and Thymus Gland corneal involvement, and visual acuity impair-
Abnormalities 43 ment are most likely to respond well, although
7 Granulomatosis with Polyangiitis/Lethal improved ocular mobility and reduction in pro-
Midline Granuloma 46 ptosis may occur in >50% of cases. Treatment,
7.1 Lethal Midline Granuloma 46 whether unilateral or bilateral, requires simula-
References 49 tion, treatment planning, dose calculation, and
care in not exceeding tolerance levels. Treatment
with IMRT can help spare critical structures.
Complications from correctly administered radi-
ation therapy are rare, although cases of radia-
tion retinopathy have been reported when large
daily fraction sizes were inadvertently admin-
istered. Cases should be selected with care,
including consultation with ophthalmologists
and endocrinologist, as all patient with thyroid
eye disease are not candidates for radiotherapy.
The implementation of secondary therapeutics
has increased the number of therapeutic options,
but radiotherapy is still prescribed in moder-
ate-to-severe Graves’ orbitopathy especially if
A. Martella (*) · Y. Qian · R. Chaudhari IV corticosteroids are contraindicated or inef-
Department of Radiation Oncology, Stanford
University, Palo Alto, CA, USA
fective. The role of radiation continues to be
e-mail: martella@stanford.edu; the object of prospective clinical investigation
yushenq@stanford.edu; rishabhc@stanford.edu (NCT02339142, NCT03098225).

Published Online: 12 May 2023
28 A. Martella et al.
Total # of
Author, year patients Treatment Results Notes
Choi and 62 24 Gy retro-orbital 40 patients (64.5%) and 46 Moderate-to-severe active
Lee (2020) XRT + low-dose oral patients (74.1%) had GO patients, retro-orbital
steroids for patients improvement in GO (Graves’ XRT improves high CAS,
with high clinical orbitopathy) at 3 and proptosis, extraocular muscle
activity scores (CAS) 6 months, respectively. At (EOM) limitation, and
6 months, 22 patients compressive optic
(68.8%) of late-active phase neuropathy. Can be
group and 24 patients (80%) considered in long-lasting
of early-active phase group active GO patients
had improvement
Li et al. 116 20 Gy retro-orbital 85 patients (73.3%) had Orbital pain, tearing, and
(2017) XRT in 2–3 weeks improvement in GO EOM dysfunction had best
delivered with IMRT symptoms, and only 4 response. Authors provide
patients (4.7%) suffered target delineation guidance
recurrence of GO symptoms
during follow-up
Hahn et al. 86 20 Gy retro-orbital 81 patients (94%) responded Authors conclude that orbital
(2014) XRT + prolonged to XRT. Of patients taking XRT is well tolerated and
corticosteroids baseline corticosteroid, 91% helps minimize the dose of
tapered off completely, and corticosteroid therapy while
remaining decreased dose improving ocular symptoms,
83%. Diplopia, visual acuity, including proptosis and
and EOM improved in 29%, diplopia
81%, and 58%, respectively
Matthiesen 211 20 Gy retro-orbital 176 patients (84.2%) had Retro-orbital XRT is an
et al. (2012) XRT improvement of pretreatment established treatment for
symptoms. Corticosteroids GO. Orbital reirradiation is
discontinued in 97.8% of beneficial for patients who
patients; 14 patients had do not respond to initial RT
reirradiation and 5 of these or have recurrence of
achieved CR and other 9 symptoms
achieved disease stabilization
Stiebel- 1367 Meta-analysis of RCT IV pulse corticosteroids Combination of XRT with
Kalish et al. comparing XRT, better than oral in reducing corticosteroids has better
(2009) medicinal therapies, clinical activity. XRT efficacy than XRT or oral
placebo, and no therapy superior for response rates of corticosteroid alone
diplopia
Prummel 88 44 patients treated with 23/44 (52%) XRT patients XRT was effective in
et al. (2004) 20 Gy retro-orbital vs. 12/44 (27%) sham XRT improving eye muscle
XRT and 44 patients patients had improvement at motility and decreasing
with sham XRT 12 months. Quality of life severity of diplopia. Less
improved similarly between follow-up treatment required
both XRT and sham XRT in XRT treated patients. XRT
patients did not prevent worsening of
ophthalmopathy. Authors
conclude that XRT is
effective in mild
ophthalmopathy
Marcocci 204 44 patients treated with Investigated long-term side Authors conclude that orbital
et al. (2003) cobalt unit and 160 effects with 5- to 25-year XRT is a safe treatment, not
patients treated with follow-up. Cataracts observed associated with increased
linear accelerator. Most in 21 patients (10%). Mild, frequency of cataract,
combined with asymptomatic retinopathy provided that a high-voltage
glucocorticoids observed in 1 of 7 patients apparatus is used. HTN
with DM and HTN, 1 of 31 (especially with DM) may be
with HTN alone, and 0 of 11 a relative contraindication
with DM alone. No tumors
observed in the 157 evaluated
by CT scan
Autoimmune Disorders 29
(continued)
Total # of
Gorman 42 One randomly selected No clinically or statistically The slight improvement at
et al. (2001) orbit treated with significant difference 12 months may be the result
20 Gy XRT and the between the treated and of natural remission or XRT,
contralateral orbit untreated orbit observed at but changes were of marginal
treated with sham 6 months. At 12 months, clinical significance
XRT. Six months later, muscle volume and proptosis
the therapies were improved slightly more in
reversed the orbit that was treated first
Mourits 60 30 patients received 18 of 30 (60%) of XRT Authors conclude that XRT
et al. (2000) 20 Gy retrobulbar XRT, patients versus 29 (31%) of should be used only to treat
and 30 patients sham XRT had improvement motility impairment. Could
received sham XRT in diplopia. Elevation not show that XRT improved
improved in the XRT group, eyelid retraction/swelling or
but other variables were proptosis
unchanged. 25% of XRT
patients spared additional
strabismus surgery
Prummel 56 28 patients received 3 Response in both groups was Double-blind randomized
et al. (1993) months of prednisone equal, largely in soft tissue trial among patients with
and sham XRT; 28 involvement and eye muscle moderately severe
received 20 Gy and motility. Side effects were ophthalmopathy. Assessment
placebo more frequent and severe in was at week 24. Authors
Prednisone was 60 mg the prednisone-treated group conclude that XRT should be
po × 2 weeks tapered the treatment of first choice,
over 11 weeks because there are fewer side
effects
Kao (1993) 21 treated 20 Gy retro-orbital No change in orbital CT Clinical indexes of
patients, XRT muscle diameter. Soft tissue orbitopathy improved at
and 6 signs improved in both 1-year follow-up but were
untreated groups. No change in not specific to treatment
controls proptosis, visual acuity, and given
intraocular pressure
Lloyd and 36 20 Gy to midplane of 3 of 36 failed to respond and No complications. FU was
Leone retro-orbital required immunosuppression 24 months
(1992) to arrest progressive signs
33 of 36 achieved
stabilization or improvement
Miller et al. 1 20 Gy via 4 MeV Patient did not respond to Authors review the literature
(1991) photons in XRT and 16 months after and point out that this 1 case
10 × 200 cGy fractions XRT had bilateral orbital of retinopathy is related to
decompression. 3 years later, radiation. They recommend a
she developed classic signs minimum follow-up of
of radiation retinopathy 3 years
Kazim et al. 84 High-dose steroids or Radiation resulted in Radiotherapy had greater
(1991) 20 Gy radiation improvement of orbital efficacy and fewer
congestion and was more complications than steroids
effective than steroids in
relieving compressive optic
neuropathy. 1 of 29 optic
neuropathy patients who
were irradiated required
decompression, 6 of 16 optic
neuropathy steroid-treated
patients required surgery
(continued)
(continued)
Total # of
Petersen 311 Group I: Radiotherapy arrested All patients had progressive
et al. (1990) 20 Gy/2 weeks progression in all but 1–6% ophthalmopathy. Minimum
II: 30 Gy/3 weeks of patients. Best responses follow-up of 12 months. No
III: 20 Gy/2 weeks were noted for: soft tissue, complications. 29% had
corneal involvement, and subsequent eye surgery
sight loss. >50% of patients
had improvement in eye
muscle function and
proptosis. No differences in
dose schedule
Appelqvist 18 12 patients had Both groups had some
et al. (1990) 4000 cGy in 362 cGy immediate and late response
fractions; 6 patients to treatment. One patient
had 2150 cGy in receiving 4540 cGy in
198 cGy fractions 12 × 378 cGy fractions lost
her vision
Schaaf 23 11 treated with Irradiated patients required
et al. (1989) steroids, 12 treated less total amount of steroids,
with steroids + 29 Gy for shorter period of time
radiation
Kahaly 297 Review article of many Results not characterized Retrospective study which
et al. (1989) treatments—Some of well with regard to radiation does not give details as to
27 patients in group IV therapy as a specific radiation
received radiation as treatment
did a few of the 10 in
group V
Wiersinga 58 44 patients received 66% had favorable response Responses observed in all
et al. (1988) prednisone; 39 patients 64% had favorable response classes of NOSPECS system
given radiation and were not dependent upon
any independent parameters
tested
Parker – Letter to Editor in response
(1988) to prior publication of
radiation retinopathy
occurring after standard
doses and delivery of
20 Gy/2 weeks. The authors
correctly point out that prior
cases of such injury have
been associated with
incorrect administration of
radiation resulting in large
daily fraction size. They
point out the rarity of such
injury and the importance of
proper delivery of treatment
Palmer 29 Radiotherapy 48% were improved, soft 13/29 underwent post-RT
et al. (1987) 20–30 Gy/2–3 weeks tissue changes improved in surgery for relief of residual
20/29 had prior 78%, proptosis improved in signs/symptoms
steroids. 8/29 had prior 52%, ophthalmoplegia
orbital decompression improved in 24%
90% no longer required
steroids
(continued)
Total # of
Marcocci 74 14 patients had cobalt Systemic steroids + RT Retrobulbar steroid dose was
et al. (1987) radiotherapy 20 Gy/2 revealed excellent/good 14 bilateral injections of
weeks + retrobulbar response in 60% vs. 30% in methyl prednisolone acetate,
injection of the retrobulbar steroid + RT 40 mg. Injections were every
corticosteroids. Then group 20–30 days for 9 months.
60 patients were Systemic steroid dose was
randomized to receive: 70–80 mg methyl
orbital RT + retrobulbar prednisolone for 3 weeks
steroids—30 patients or with gradual taper for a total
orbital RT + systemic of 5–6 months. Retrobulbar
steroids—30 patients steroids should only be used
All RT was via cobalt, if systemic steroids are
200 cGy/day contraindicated. No patient
was treated with RT alone
Olivotto 2000 cGy/10 fractions 26/28 (93%) responded; No complications. Mean
et al. (1985) over 12 days using 19/28 (68%) good to follow-up 17 months
4 MeV linear excellent response; 14/28
accelerator to have undergone post-XRT
retrobulbar area surgery; 24/28 (86%) spared
Half beam block long-term high-dose
technique to eliminate corticosteroids
lens exposure
Hurbli et al. High-dose prednisone 34/46 (74%) motility No morbidity
(1985) (60–120 mg/day). problems improved; 12/28
Those with poor (53%) patients with
response underwent symptoms greater than
radiotherapy to orbit 6 months responded
2000 cGy/10 fractions compared to 13/18 (72%)
over 12–14 days. Beam whose problems were
angled 5° posteriorly to present far less than
avoid contralateral lens 6 months (not significant).
10 of 14 with optic
neuropathy improved, but 4
had recurrences
van 2000 cGy in 10 Decrease in proptosis. Median duration of eye
Ouwerkerk fractions of 200 cGy in Increase in visual acuity. All symptoms before
et al. (1985) 2 weeks using 4 MeV patients could be tapered off irradiation—12 months.
photons to orbit. Most prednisone Follow-up ±4.5 years
patients were also
given prednisone
30–60 mg/day
Kinyoun 4 Intended: All 4 developed radiation Major dosimetric error
et al. (1984) 2000 cGy in 10 retinopathy, decreased occurred in which patients
200 cGy fractions to acuity, and 3/4 are blind actually received 400 cGy to
orbit the midplane each day, rather
Actual: than the prescribed 200 cGy
4000 cGy in 10 Thus, a total dose of
400 cGy fractions 4000 cGy/10 fractions @
400 cGy/fraction
Brennan 14 2000 cGy in 10 days to 13/14 had reduced soft tissue Follow-up:
et al. (1983) orbit inflammation; 12/14 had 6 months to 3 years
decreased proptosis 1–3 mm. No sequelae and no
Myopathy stabilized recurrences
permitting subsequent
strabismus surgery
(continued)
(continued)
Total # of
Yamamoto 6 Steroid therapy, Decrease in proptosis, Improvements noted 3–7
et al. (1983) supervoltage orbital decrease in muscle months after therapy.
radiotherapy enlargement. Duration of response <18
2000 rad/10 days months
Yamamoto 9 Radiation therapy plus 4—good results No long-term follow-up
et al. (1982) steroid therapy, 1—fair results
plasmapheresis to orbit 4—no response at 4-week
Radiation: evaluation
2000 rad/10 days
10/200 rad fractions
Teng et al. 20 2000 rad/12 days in 7/20 (35%) showed response Long-term follow-up <25
(1980) 200 rad fractions to within 3 weeks months
orbit using 4.2 MeV 4 patients (20%) minimal Patients had long duration of
linear accelerator response eye symptoms prior to
9 patients (45%) unchanged therapy
Trobe 6 1500–2000 rad in 10 6/12 eyes were improved at 5/6 responding eyes had
(1978) daily fractions using 8-week evaluation rapid decline in vision just
4 MeV photons to orbit prior to XRT
Covington 7 2000 rads/2 weeks 5/7 improved with 3 months No complications
et al. (1977) using 6 MeV linear of treatment
accelerator to orbit
Ravin et al. 37 Radiotherapy: 1500 r Class 3 patients (4): Classification of ocular
(1975a, b) (in air)/10 F/10 days. No significant decrease in changes of Graves’ disease:
Lateral orbital fields exophthalmometer 0—No signs or symptoms
6 × 7 cm lead shield to measurement 1—Only signs (upper lid
protect the lens Class 4 patients (18): retraction and stare, with or
2/18 progressed to class 5 without eyelid lag and
disease after treatment. 1 proptosis), no symptoms
patient with limitation of 2—Soft tissue involvement
movement prior to treatment (signs and symptoms)
gained full range of motion 3—Proptosis
Class 5 patients (6): 4—Extraocular muscle
5/6 visual acuity was good involvement
before and after treatment 5—Corneal involvement
1/6 with severe exposure 6—Sight loss (optic nerve
keratitis was not improved— involvement)
subsequently underwent
corneal transplantation
Class 6 patients (9):
9/9 visual acuity improved
(within 2 weeks in most
patients) 7/8 optic nerve
congestion improved within
4 months. 4/5 scotomas
resolved in 1–6 months
Donaldson 23 Radiotherapy: 2000 r Overall clinical assessment: All 23 patients had previous
et al. (1973) (total orbital 15/23 (65%) good-excellent treatment for thyrotoxicosis.
dose)/10 F/2 weeks results, 6/23 (26%) fair 16 had received previous
4–6 MeV fields: results, 2/23 (9%) no treatment for
Left and right lateral response There was good ophthalmopathy (14 of these
roughly triangular in agreement between the had corticosteroids)
cross section to cover the clinical assessment and the
muscular cone of the change in ophthalmopathy
globe and nothing else index
Fields were angled to
avoid the contralateral lens
(continued)
Total # of
Blahut et al. 18 1500 r 13/18 (72%) had a decrease 4/13 (31%) who obtained a
(1963) (air)/10 F/10 days to in exophthalmometer decrease of 2 mm or more
each field. Technical readings of 2 mm or more in during treatment showed a
details: at least one eye (6 in 2 eyes) decrease in exophthalmos to
250 kV, 13 mA, during the course of therapy pretreatment levels within
0.44 mm Sn, 0.25 mm 1/18 no decrease in 6 months after treatment
Cu plus 10 mm Al exophthalmometer readings,
filtration, HVL 2.7 mm but decrease in chemosis and
Cu, FSD 50 cm subjective complaints
Fields: Two opposing 1/18 decrease of 2 mm in
lateral fields approx. exophthalmometer reading
7 × 7 cm each to 2 months after therapy
include the pituitary,
the lower part of the
hypothalamus, and the
retrobulbar tissues
Gedda and 19 Pituitary and/or orbital Pituitary and orbital
Lindgren radiotherapy irradiation (16 patients)
(1954) Orbital irradiation: 10/16 (63%) lacrimation,
900 r (skin dose) photophobia, and
6–9 F/6–9 days to each ophthalmoplegia
field followed after an disappeared. 6/7 eyelid
interval of 4–5 weeks edema disappeared, 2/2
by a second course of chemosis disappeared, 10/10
200–900 r hyperthyroid patients
Technical details: became symptom free
170 kV, 15 mA, Additional irradiation to the
0.5 mm Cu plus 1 mm anterior part of the orbit was
Al filtration, HVL given to those 6 patients who
0.9 mm Cu, FSD did not respond. The results
50 cm, lateral fields, of this were:
10–15 cm2 4/5 disappearance of eye
Pituitary irradiation: signs
15,000 r (skin dose) 5/6 eyelid edema
4–5 F/4–5 days to each disappeared
field followed in 2/2 chemosis disappeared
5 weeks by a second Orbital irradiation only (3
course of 600–900 r patients)
Technical details: 2/3 disappearance of eye
170 kV, 15 mA, sign
0.5 mm Cu, FSD, 1/3 no response 11/19 had
52–60 cm, 4 temporal previous thyroidectomy for
fields, 5 × 6 cm hyperthyroidism
Beierwaltes 28 X-ray to the pituitary, Follow-up All patients treated presented
(1953) 1550 r/10 F/10 days to 9 months–12 years; 13/28 2 or more eye signs of
each field, 200 kV, (46%) decrease of 2 mm or malignant exophthalmos. 4
25 mA, 0.5 mm Cu more in exophthalmometer patients exhibited no
plus 1 mm Al filtration, measurements in at least one evidence of thyroid disease
HVL, 1 mm Cu, FSD eye. Average of 19 months
50 cm required for maximum
remission
10/12 decreased lid edema,
7/11 decrease or
disappearance of bulbar
conjunctival edema
(continued)
(continued)
Total # of
Jones 29 Varied dosage Follow-up of 9 months to 22 patients had progressive
(1951) schedules: 5 years exophthalmos
200 r (skin True progressive 7 patients had thyrotoxic
dose)/56 days to exophthalmos (22 patients) ophthalmopathy. Sequelae:
1000 r/14 days 1. Malignant exophthalmos Cataracts (1)
Technical details: 2/2 exophthalmos
190–250 kV, 15 mA, disappeared
HVL1.3-1.85 mm Cu, 2. Chronic progressive
FSD25-60 mm. Fields: exophthalmos
anterior and lateral 9/19 (47%) complete or
orbital. The anterior moderate regression of
field extends from the exophthalmos
supraorbital ridge to 7/19 (37%) slight regression
the molar region of exophthalmos
(8 × 6 cm). The lateral 3/19 (15%) no regression,
field may be restricted 20/20 edema greatly
to the bony orbit diminished or abated
(4 × 6 cm). Lead shield 15/18 ocular movements
to protect the lens in normal or improved
mild cases Thyrotoxic exophthalmos (7
patients)
3/7 some decrease in
exophthalmos and
ophthalmoplegia, 2/7
substantial relief from
conjunctivitis
2 Hashimoto’s Thyroiditis against thyroid antigens, diffuse lymphocytic infil-

tration of the thyroid gland, and follicular destruc-
Hashimoto’s thyroiditis is characterized by tion. Hashimoto’s thyroiditis is typically managed
autoimmune-mediated destruction of the thyroid with thyroid hormone replacement. Radioactive
gland leading to gradual thyroid failure. iodine ablation has been explored as a potential
Pathogenesis is mediated by autoantibodies option for goitrous Hashimoto’s disease.
Total # of
Tajiri 13 13 mCi of I-131 58.7% reduction from baseline All were cases of goitrous
(2006) administered 2–6 in size of goiter Hashimoto’s thyroiditis
times, at an interval
of 1–6 months
Papapetrov 12 Thyroxine (long- Significant decrease in goiter All were cases of
et al. (1972) term therapy average size. In 4 patients, the thyroid Hashimoto’s thyroiditis
of 9.9 years) was not palpable
6 weeks after stopping therapy,
11 patients were clinically
hypothyroid
(continued)
Total # of
Heimann 178 1. Surgery (58), 11 1. Complications of surgery: Chronic thyroiditis
(1970) patients had also Post-op growth of goiter
been treated by (15.5%)
thyroid hormone Hypoparathyroidism (3.4%)
2. Thyroid hormone Permanent unilateral vocal cord
(130) paralysis (3.4%)
3. No treatment (1) 2. Subacute cases 22/29 total
regression of disease. Chronic
cases 13% no change in status,
87% regression of goiter
Vagenakis 6 Prednisone Dramatic and marked relief of All were cases of acute
et al. (1970) symptoms in all cases. No nonsuppurative thyroiditis
recurrences when prednisone
was continued until the 1-131
uptake had returned to normal
Lindem and 46 Surgery—near-total No follow-up data Type of thyroiditis:
Clark thyroidectomy. Oral Hashimoto’s disease (89%)
(1969) thyroid given after Riedel’s struma (4%)
surgery in all patients Granulomatous thyroiditis
(7%)
Indication for surgery was
a mass with carcinoma as a
possibility in 5%
Thomson 1 Steroids Good therapeutic response, but a Riedel’s thyroiditis “In
et al. 1968 (betamethasone) hard goiter developed when an view of the satisfactory
attempt to discontinue the clinical response of the
steroid therapy was made first patient, a trial of
steroid therapy would
seem indicated in this
condition where surgical
management may be
hazardous”
Varl et al. 6 I-131 (diagnostic Immediate disappearance of All were cases of subacute
(1968) dose of 40–50 μCi) pain, temperature decrease, diffuse thyroiditis
thyroid became softer, and signs
of inflammation gradually
regressed
Quick improvement in 3 cases
of local thyroiditis and in 2
cases of thyroiditis in a toxic
thyroid nodule
Blizzard 3 Cortisone Within 20–40 days after Hashimoto’s thyroiditis
et al. (1962) cortisone treatment, all 3 “Signs and symptoms recur
patients became euthyroid and when therapy is
the glands were no longer discontinued. Desiccated
palpable. The goiters recurred thyroid remains preferable
when the steroid dosage was for the treatment of
reduced patients with this disease”
(continued)
(continued)
Total # of
Murray 3 Prednisone 3/3 rapid diminution in size of Hashimoto’s thyroiditis
(1958) gland and an improvement in “It is suggested that steroid
the associated biochemical therapy has little place in
abnormalities as long as the treatment of this
treatment was continued. There condition, but that if
was no change in the objective combined with the
evidence of hyperthyroidism administration of thyroid it
might be of value when
rapid relief of symptoms
due to pressure of an
enlarged gland is
required”
Furr and 62 1. Radiotherapy 1. Occasionally, a rapid decrease All were cases of struma
Crile (after needle biopsy), in size within a few days, but lymphomatosa
(1954) 450–2400 r (11 usually a progressive
patients plus diminution, the goiter reduced
desiccated thyroid in 50% in 2 months
6 of those patients) 2. 1/12 decrease in size in less
2. Desiccated thyroid than 1 month
(12 patients) In most cases, size decreased
3. Cortisone (4 50% in 4–6 months
patients plus 3. 4/4 decrease in size within
desiccated thyroid in 1–2 months
3 of those cases)
Lindsay 37 1. Surgery (25) 1. 10/13 became hypothyroid Granulomatous or
and Dailey 2. Nonoperative and required therapy with giant-cell thyroiditis
(1954) groups (12) desiccated thyroid. No known
recurrences of thyroiditis
(follow-up of 4 months,
15 years)
2. 5/12 completely free of pain/
tenderness within 4 weeks
The glands of 10 patients
became essentially normal
although slightly firm
Crile and Authors state that they
Schneider have employed
(1952) radiotherapy with doses of
600–1000 r as a standard
therapy for subacute
thyroiditis, which produces
relief within 1–2 weeks.
But they employ ACTH or
cortisone in cases in which
a quicker result (48 h) is
desired
Struma lymphomatosa is
treated almost exclusively
with desiccated thyroid
3 Immunosuppression TLI is an effective and relatively nontoxic

mode of immunosuppression in selected circum-
The current use of total lymphoid irradiation stances with the potential clinical advantages for
(TLI) as immunosuppressive therapy for nonma- patients who have advanced autoimmune diseases
lignant disease is experimental and has been uti- and for preparation of high-risk patients for organ
lized in the preparation for allogeneic organ transplantation. It is an experimental alternative or
transplantation, in the treatment of autoimmune complement to pharmacological immunosuppres-
diseases, and in the treatment of neurological dis- sion. Optimal fractionation schemes and total dose
orders considered to have an immune-mediated requirements are not clearly determined. Its use
pathogenesis. should typically be restricted to controlled clinical
trials undertaken in major medical centers.
Total # of
Author, year patients Treatment Results Comments
Hume and 4 Sublethal total-body 2/4 died as a direct Renal transplants
Wolf irradiation consequence of irradiation,
(1967) 2/4 still alive
Hamburger 43 Irradiation alone and/or drug Irradiation alone: Renal transplant
et al. therapy (Imuran or 12 early failures
(1965) 6-mercaptopurine). Some 2 lengthy tolerance and
patients received a second survival
transplant Irradiation plus drugs:
8 well, 1–34 months
1 progressive renal failure,
second transplant at
22 months
3 died at 9–23 months
Drugs alone:
2 early failures
16 well at 1–10 months
Woodruff 1 2 days prior to transplantation, 16 days after irradiation, Renal transplantation
(1964) the patient received 150 r there was a large drop in
minimum central dose blood platelets
whole-body irradiation plus All types of leukocytes
100–110 r localized irradiation disappeared from the
to the spleen and lower right patient’s blood. Patient
abdomen developed a fatal septicemia
11 days after transplantation,
the patient was given an
additional 50 r whole-body
irradiation
Morgan 6 Whole-body irradiation 3/6 died within 26 days Renal transplantation
(1964) (100–400 r) prior to 1/6 died at 30 months
transplantation 2/6 still alive, one at
27 months
Woodruff 6 Pre-op irradiation plus post-op 4/6 alive (at 3–9 months, 1 Renal transplant
et al. administration of patient has excellent renal
(1963) antimetabolite. Pre-op function)
irradiation (100–200 r to 2/6 died, 1 at 2 months
spleen and graft site: 2 or (Imuran intoxication) and
4 MeV) one at 12 days post-op
(continued)
(continued)
Total # of
Shackman 6 Pre-op total-body irradiation Prolonged survival in 1 Renal transplant
et al. plus post-op local irradiation patient
(1963) in 2 patients
Post-op local irradiation only
in 2 patients
Pre-op total-body irradiation
only in 2 patients
Hume et al. 6 1. Total-body irradiation 1. 1/4 transplant function Renal transplants
(1963) (150–300 r) plus post-op excellent at 5 months
irradiation to the transplant 2/4 died within 34 days
(total dose 100–500 r: 4 1/4 transplant function
patients) declining at 6 months
2. Post-op irradiation to the 2. 2/2 transplant function
transplant only (600 r/4 F: 2 failed
patients)
Murray 12 Total-body irradiation 6–700 r 11/12 died (2 receiving Renal transplants; 2
et al. (2 MeV) followed by bone marrow transplants died from patients had absence of
(1962) marrow infusion in the 2 sepsis and infection; 5 others renal tissue following
patients with absence of renal showed excellent early renal injury or removal of
tissue. 200–450 r function, but there was a solitary kidney. 10
(250 kV)/l–3 F/max of 8 days rapid cessation of function in patients were in
to the other 10 patients. 3–6 days) preterminal state from
Transplant was done on the 1/12 alive and well at renal disease. 6 of the
day of or the day following 3.5 years patients were reported
the last X-ray treatment previously
Hamburger 6 Total-body irradiation. 3/6 early rejection Renal transplants
et al. 430–460 r (central (25 h–21 days)
(1962) dose)/5 days (approximately 3/6 prolonged tolerance
220 r on first day and 220 r on (6 months–2.5 years)
next 2–5 days).
Transplantation was done on
the day following the last
irradiation treatment
Tubiana 5 Whole-body irradiation 3/5 alive with functioning
et al. 400–450 r/1–2 F kidney at 5–22 months
(1961) Some patients received 1/5 died from hepatic
additional irradiation to the metastasis at 5 months,
spleen kidney was functioning
2 patients also received 1/5 died at 50 days of
additional irradiation complete medullary aplasia
2–3.5 months post-op
Total # of
Author, year patients Site and age of patients Treatment Results Notes
Tallaj et al. 73 Total lymphoid irradiation for 80 cGy twice per Short-term decrease in hazard for rejection Increased cumulative rejection over the
(2011) recurrent rejection or rejection week for 5 weeks in first 12 months posttransplant long term; 7 patients developed
with hemodynamic compromise myelodysplasia or acute myelogenous
heart-transplant patients leukemia
Ghadjar et al. 7 Tailored total lymphoid Mean dose of Rate of rejection episodes significantly 2 patients had severe infection during
(2010) irradiation in heart-transplant 6.4 Gy (range improved with TLI TLI and 1 patient developed a
Autoimmune Disorders
patients 1.6–8.8) lymphoproliferative disorder

Lim et al. 6 Total lymphoid irradiation to 6 4.5 Gy in 4 Significant improvement in allograft Acute and late toxicity was tolerable
(2007) patients with recalcitrant allograft fractions rejection along with decreased dose of
cardiac transplant rejection immunosuppressants
Madden et al. 11 Total lymphoid irradiation in 8 Gy in 10 fractions Each patient had a significant improvement 3 patients developed opportunistic
(1999) heart-transplant patients with in clinical response and in ventricular infection and 1 patient developed
severe allograft rejection performance within 2 months of lymphoproliferative disorder
commencing TLI
Wolden et al. 47 Total lymphoid irradiation for 8 Gy in 10 fractions Improvement in rejection rates after TLI; 2 patients developed malignancy;
(1997) intractable allograft rejection in decrease in prednisone requirement; the ratio prophylactic protocol was abandoned
37 patients and prophylactic in of helper to cytotoxic-suppressor T cells
10 patients decreased during TLI
Waer et al. 20 Total lymphoid irradiation for 2000–3000 r in 16/20 patients alive, 15 with functioning 12 patients had rejection episode,
(1985) cadaveric renal transplantation 100 r fractions grafts in 2-year follow-up managed with prednisone. Other 8
patients had rejection episode requiring
ATG, cyclosporin, or azathioprine
Kian Ang et al. 17 Total lymphoid radiation for 20–30 Gy in 1 Gy 6 patients survive more than 1 year and 7 2/13 patients had repeated rejection
(1985) cadaveric renal transplantation fractions patients survive less than a year with episodes necessitating cyclosporin A. 4
(diabetes) functioning kidney graft. Reduced amounts patients died of pericardial tamponade
Ages 26–55 years of steroids and azathioprine were required infection and other causes
Levin et al. 28 Total lymphoid irradiation for 2000 r in 100 r 25 patients were evaluable. Actuarial graft Patients managed with low-dose
(1985) cadaveric renal transplantation fractions to mantle, survival at 18 months was 77% maintenance prednisone
Ages 22–66 years spleen, and inverted Y 4 patients died and 6 grafts were lost
Vanrenterghem 10 Total lymphoid irradiation for 2000–2500 r in All patients survived with 9/10 grafts Reduced need for steroids in most
et al. (1984) cadaveric renal transplantation. 100 r fractions functioning with 12-month follow-up patients
Ages 32–51 years
Najarian et al. 22 Total lymphoid irradiation for 1050–4050 r in 78% actuarial patient survival and 74% 17 patients had complications requiring
(1982) human renal transplantation. 100–125 r fractions well-functioning grafts at 2-year follow-up interruption of therapy and 4 patients
Ages 5–55 years to mantle and died, 2 with lymphoma. Recommend
inverted Y 2500 r fractionated TLI followed by
39
simultaneously transplantation with 2 weeks of XRT

3.1 Local Field Irradiation in Renal of immunosuppressive agents. Prospective ran-

Transplantation domized studies fail to demonstrate improvement
in engraftment over nonirradiated controls. The
In the setting of renal transplantation, local radia- continued use of this technique in non-protocol
tion has been used to prevent rejection after failure investigative studies is not warranted.
Total #
of
Ramanathan 5 Local allograft 4.5 Gy in 1.5 Gy 6 of 9 treatments
et al. (2015) irradiation for severe fractions were successful at
resistant rejection rescuing the
after liver transplant allograft. Trend
toward later onset of
rejection
Fallahzadeh 6 Local renal graft 600–800 cGy in 1-month graft
et al. (2014) irradiation for 150–200 cGy survival of 83%;
treatment of acute fractions 1-year graft survival
rejection after failure of 17%
of
immunosuppression
Wahl et al. 33 Local graft irradiation Median dose Median follow-up
(2006) for acute renal 800 cGy in 200 cGy was 25 months.
allograft rejection fractions 20.6% were alive
refractory to with functioning
immunosuppressants graft. Median
dialysis-free survival
was 3.6 months
Halperin 67 Renal allograft 300–1200 r to kidney Of 53 kidneys
et al. (1984) irradiation. Mean age in 150 r fractions. irradiated because of
37 years Mean dose 600 r failure of standard
immunosuppression
for acute rejection,
21% of allografts
functioned 1 year
after transplant
Pilepich 62 (64 grafts) Renal graft Methylprednisolone No difference in A prospective
et al. (1983) irradiation in acute XRT 34 grafts reversal of graft randomized
rejection, any age randomized to XRT rejection or graft study
525 r given in 175 r survival in the
fractions every other irradiated grafts as
day compared to sham
controls
Peeples et al. 44 Renal graft irradiation 600 r/course Rate of successful Nonrandomized
(1982) for rejection. Ages 4 meV photons renal function was: study
16–60 years. Mean 150 r fractions 52% among 29
age 41 years patients who had 1
course of XRT
60% among 15
patients with 2–4
courses of XRT
60% among 50
patients with steroids
only and no XRT
(continued)
Total #
of
Besarab 83 (89 cadaver donor 450 r given in three Prophylactic Prophylactic
et al. (1982) grafts) 150 r fractions on irradiation and ATN irradiation to
Prophylactic renal alternating days, decreased graft recipients,
graft irradiation along along with Imuran, survival, effects were alternated
with acute tubular prednisone, additive randomly, but
necrosis (ATN). methylprednisolone, not double blind
Average age 36 years and antilymphocyte
globulin (AGC)
Nakajima 158 (205 renal transplants, i.v. Local radiation did Significant sepsis
et al. (1977) 179 rejection methylprednisolone not contribute to was observed in
episodes). Renal graft with and without improved graft those patients
irradiation during XRT 600 r given in survival or mortality receiving more
acute rejection four 150 r fractions than 5 g
methylpred
nisolone
Godfrey and 36 Renal graft irradiation 1/2 of patients At 3 years, there was Randomized
Salaman at the time of first received high doses no difference in the study
(1977) rejection of steroid drugs two groups in
1/2 received 600 r in response to
four 150 r fractions treatment, graft
on alternate days survival, or
transplant function.
No benefits from
XRT were observed
Drenguis 178 Renal graft irradiation 4.5 Gy given in three Of the irradiated
et al. (1977) in acute rejection. 1.5 Gy fractions on kidneys, 61% were
Ages 9–54 years. alternate days along functioning at
Mean age 27 years with systemic 6 months, 58% at
immunosuppressive 12 months, and 49% at
therapy 18 months
4 Lupus Erythematosus (Lupus ticularly in cases refractory to medical man-

Nephritis) agement. Data is mixed with respect to the
efficacy of the treatment and concerning tox-
Radiotherapy (total lymphoid irradiation) has icities noted.
been used in the setting of lupus nephritis, par-
Author, Total # of Site and age of

year patients patients Treatment Results Notes
Strober 15 Total lymphoid 2000 r in 13/15 patients alive with Update and extension
(1987) irradiation for 4–6 weeks in stable renal function. of series reported by
diffuse lupus sequential TLI Patients had improved Strober et al. Ann Int
nephritis, moderate renal function. 4 patients Med 1985
to high chronicity had steroids withdrawn
index on renal with resolution of
biopsy, and nephrotic syndrome
nephrotic
syndrome
(continued)
(continued)
Author, Total # of Site and age of
Ben- 2 Total lymphoid 2000 r in 200 r No beneficial clinical After 800 r
Chetrit irradiation 23 and fractions to effects regardless of subdiaphragmatic XRT
(1986) 34-year-old mantle, adequate in one patient, treatment
patients who had followed by immunosuppression was discontinued
failed conventional 2000 r in 200 r Proteinuria increased, Both patients developed
treatment fractions to creatinine clearance major complications
spleen and decreased and 1 died within
inverted Y 2 weeks of XRT from
florid nephritis.
Experimental therapy
Strober 10 Total lymphoid 2000 r in 200 r All patients had increase in Side effects were
(1985) irradiation fractions to serum albumin and minor. Experimental
19–43 years of age mantle followed decrease in serum therapy
with severe by 2000 r in anti-DNA antibodies with
intractable 200 r fractions increase in serum
glomerulonephritis to inverted Y complement levels
and spleen 8/10 patients had
(pelvis omitted improvement for
in females). 12–44 months with
Kidneys not decrease in serum
irradiated creatinine in 3 and
stabilization in 7 patients
All patients had less
urinary leakage of albumin
5 Multiple Sclerosis indicates limited benefit of the use of TLI in this

setting.
In the setting of multiple sclerosis, total lym-
phoid irradiation has been used for the treatment
of chronic progressive multiple sclerosis. Data
Total #
of Site and age of
Author, year patients patients Treatment Results Notes
Wiles et al. 27 Total lymphoid 1980 cGy in 12 No benefit in disease
(1994) irradiation fractions progression
Devereux 20 Total lymphoid 1980 r in 180 r TLI vs. sham treated: Update of paper by
et al. (1988) irradiation in fractions to mantle Functional scale Cook et al. Lancet
adults with mean and spleen assessment 1986. Prospective,
age of 44 years followed by 84% vs. 45% randomized,
and chronic 1980 r in 180 r (p < 0.03)—12 months double-blind study
progressive fractions to 72% vs. 37% compared against
multiple inverted Y (p < 0.03)—18 months sham-irradiated
sclerosis (including pelvis) 56% vs. 26% controls
(NS)—24 months
50% vs. l3%
(NS)—30 months
Reduction in lymphocyte
count 3 months
postirradiation (p < 0.02)
(continued)
Total #
of Site and age of
Cook et al. 45 Total lymphoid 1980 r total Clinical effects: Update of 1986
(1987) irradiation lymphoid Patients with sustained article. All patients
Adults irradiation vs. lymphocyte counts had chronic
20–60 years sham-TLI <900 mm3 for prolonged progressive multiple
periods after XRT had sclerosis
less rapid progression of Prospective,
disease over 3 years than randomized
patients with lymphocyte double-blind study
counts >900 mm3
(p < 0.01)
Kolar and 1 Total lymphoid 200 r in 200 r Progression of clinical Transient clinical
Hornback irradiation. Age fractions over course improvement with
(1986) 37 years 59 days transient
normalization of
OKT8/OKT4 cell
ratio during
irradiation, but
overall progression
Cook et al. 20 Total lymphoid 1980 r in 180 r Clinical effects: Prospective,
(1986) irradiation. fractions to Longer time to sustained randomized,
Adults with mantle, followed progression than controls double-blind study
mean age of by 1980 r in 180 r (p < 0.05) and less compared against
42.9 years fractions to functional decline, sham-irradiated
having chronic inverted Y and particularly in patients controls. Minor side
progressive spleen (pelvis with sustained effects
multiple excluded) lymphocytopenia Experimental therapy
sclerosis
Tourtellotte 20 Cranial-spinal 1200 r or 1800 r in No neurological Transient reduction
(1980) irradiation. Ages 150 r fractions improvement, change in in the rate of de novo
30–58 years activity of the disease, or CNS IgG synthesis
persistent adverse effects with 1200 r;
enhancement
following 1800 r
6 Myasthenia Gravis myasthenia gravis include acetylcholinesterase inhib-

and Thymus Gland itors, chronic immunosuppressive agents, rapid short-
Abnormalities acting immunomodulating agents, and surgery. While
radiation was historically served as an alternative
Myasthenia gravis (MG) is an autoimmune disease treatment option for thymoma-associated myasthenia
resulting from autoantibody to nicotinic acetylcho- gravis, in the modern era, it does play a role in the
line receptors (AChR) at the neuromuscular junction. primary treatment setting. Modern institutional series
There is a pathologic association with thymoma, as explore the utility of adjuvant radiation after thymec-
10–15% of myasthenic patients have underlying thy- tomy, as well as in the primary setting with stereotac-
moma, and in turn 20–25% of patients with thymoma tic ablative radiation therapy for patients not amenable
have myasthenia gravis. Modern core therapies for to surgery.
Total # of
Lu et al. 181 with Thymectomy with (157 Clinical remission rates of No difference in overall
(2018) synchronous patients) or without (24 MG: survival and disease-
myasthenia patients) radiation 33%—adjuvant RT within free surviva
gravis and 4500–5500 cGy in 1 month
thymoma 25–30 fractions 25%—adjuvant RT within
3 months
23%—no adjuvant RT
Lee et al. 1 SBRT Rapid resolution of Complete resolution of
(2016) myasthenia gravis symptoms anterior mediastinal
mass by 2 months
45 5420 cGy to 4—improved
mediastinum 4—progressed
34—no change
2—cholinergic crisis
Durelli 12 Total-body irradiation 6/12 patients with objective Durable response
et al. 180–230 r clinical improvement (>2 years) in 5/12
(1993) patients
Arakawa 30 Thymectomy with 7/9 patients with MG had 5-year survival higher in
et al. adjuvant radiation symptom control patients without
(1990) 3000–5870 r myasthenia gravis at
presentation
Currier 28 3000 r to mediastinum 16—improved Without thymoma:
et al. Median age: 4—improved on steroids Median follow-up of
(1983) 40 years 4—no change 8 years. All had failed
Ages 4—died previous optimum
11–74 years, anticholinesterase
19 females therapy
and 9 males
2 females Total-body irradiation Dramatic and sustained
150 r over 5 weeks improvement
215 r fractions/week
Goldman 26 1. Radiotherapy 1. 4/10 alive, average life All patients had
et al. (1000–6061 r) either duration of 7.5 years since the myasthenia gravis and
(1975) alone or in combination onset of illness invasive thymoma.
with a steroid preparation 2. 7/11 alive, average life Malignancy was
or cytotoxic agent or duration of 6.25 years since removed at thoracotomy
both (10 patients) the onset of illness if this could be done
2. Prednisone or ACTH, 3. 2/2 alive, average life safely. All patients
either alone or in duration of 4 years since the received some form of
combination with onset of illness anticholinesterase
radiation therapy and/or 4. 3/3 alive, average life during their illness.
cytotoxic agents (11 duration of 8.5 years since the There was no difference
patients) onset of illness in tumor response to
3. High-dosage alternate radiation or
days, prednisone and chemotherapy in
radiation therapy (2 reference to tissue type
patients)
4. Cytotoxic agents in
association with radiation
therapy and/or steroid
preparation (3 patients)
(continued)
Total # of
Desevilla 1 Radiotherapy: 3680 r The anterior mediastinal mass Metastatic thymoma
et al. anteriorly and 1040 r slowly decreased in size and with myasthenia gravis
(1975) posteriorly to the patient was well for and pure red cell aplasia
mediastinal mass approximately 6 months when in a 55-year-old man
(midline dose of the patient was readmitted
2430 r)/2 weeks, Co60 with weakness and increasing
3000 r/2 weeks to left dyspnea. No response of red
ilium cell aplasia to steroids or
cyclophosphamide
Weissberg 15 1. Resection with or 1. 5/11 significant remission Thymoma and
et al. without radiotherapy of myasthenia myasthenia gravis.
(1973) (11 patients) 2. 1/3 significant remission of Tumor was benign in 8
2. Radiotherapy alone myasthenia patients, malignant in 7.
(3 patients) No patient experienced a Duration of remission
permanent remission varied between
3 months and 5 years
Vessey and 382 Minimum of 3-year No thymoma (317)
Doll follow-up These data provide no
(1972) 5 patients died from evidence that adult
extrathymic tumors, 5.5 thymectomy is followed by an
would have been increased risk of neoplastic
expected based on the disease
national experience. 5
others developed
nonfatal extrathymic
tumors
Schulz and 72 1. Thymic irradiation 1. Without tumor: 19/35 Without thymoma (45).
Schwab only (54%) improved With thymoma (27)
(1971) 2. Thymic irradiation With tumor: 6/10 (60%)
and thymectomy improved
2. Without tumor: 13/19
(68%) improved
With tumor:
5/8 (62%) improved
128 1. Thymectomy without 1. 44/63 (70%) improved These data include
irradiation (63) 2. 57/65 (88%) improved patients from the
2. Thymectomy with current study and from
irradiation (65) a previous study by one
of the authors (Schwab)
Kreel et al. 127 With thymoma: With thymoma: With benign hyperplasia
(1967) 1. No treatment (15) 1. 4/15 (27%) living longer (60)
2. X-ray only (16) than 1 year With thymoma (67)
3. Surgery only (23) 2. 7/16 (44%) living longer Authors concluded that
4. Surgery and X-ray than 1 year radiotherapy as the sole
(13) 3. 10/23 (44%) living longer form of treatment is of
With benign than 1 year limited use. Also,
hyperplasia: 4. 5/13 (38%) living longer preoperative
Thymectomy than 1 year radiotherapy did not
With benign hyperplasia: seem to be useful
42/60 remission or
improvement
(continued)
(continued)
Total # of
Phillips 7 Radiotherapy, Initial response: 4/7 had thymic
and 3000–5500 r, to the 6/7 complete remission or neoplasm
Buschke thymus improvement
(1967) Present state:
3/7 complete remission or
improvement, 2/7 died of
tumor
Wolf 1 Partial excision of Patient improved. Almost Patient had myasthenia
(1966) tumor plus post-op complete remission of gravis and thymomal
irradiation (3000 r) plus myasthenia at 10-month
drug therapy follow-up
7 Granulomatosis frequently granulomatosis with polyangiitis). It is

with Polyangiitis/Lethal presumed that many of the historical publications
Midline Granuloma evaluating lethal midline granuloma consisted of
patients with lymphomatous malignancy, and this
Granulomatosis with polyangiitis (previously author will not expand on contemporary trials
known as Wegner’s granulomatosis) is a vasculitis evaluating this lymphomatous entity. Thus, the
with necrotizing granulomatous inflammation reader is cautioned to the importance of differen-
involving the upper and lower respiratory tract, tiating lethal midline granuloma as a probable
kidneys, and systemic vasculature. “Lethal mid- lymphoproliferative disorder from that of an
line granuloma” (also referred to as idiopathic inflammatory condition, emphasizing the impor-
midline destructive disease) is an antiquated term tance of securing modern immunohistochemical
used to describe localized, progressive destructive studies to assist in establishing the diagnosis. Of
lesions of the nose, paranasal sinuses, palate, and note, radiation therapy is reserved for refractory
midfacial tissues. This term is now understood to granulomatosis with polyangiitis and the treat-
be mostly composed of non-Hodgkin’s lym- ment is used infrequently. Most recent literature is
phoma (most commonly extranodal natural limited to case reports given its rarity of being
killer/T cell lymphoma (ENKL), and much less managed with radiation therapy.
7.1 Lethal Midline Granuloma
Total # of
Wei et al. 1 30 Gy XRT with 9 MeV Eyelid lesion resolved Author concludes that
(2021) electrons to eyelid. XRT field XRT can be considered
defined as 5 mm areal expansion for granulomatosis with
polyangiitis after failure
of standard treatments
1 30 Gy XRT with IMRT to base Complete clinical Histopathology confirmed
of nose response at 12 months Wegener’s
granulomatosis. Slow
regression observed
Poorter 1 52 Gy XRT to the nasal cavity, 5 years post Patient found to have
et al. (2007) and “re-irradiation” of the re-irradiation with no idiopathic midline
posterior pharyngeal wall signs of tumor destructive disease
recurrence (IMDD), also known as
lethal midline granuloma.
No evidence of Wegner’s
or lymphoma
(continued)
Total # of
Neviani 1 Two courses of XRT delivered at No clinical or 42-year-old patient with
et al. (2002) a 1-month interval: 20 and 26 Gy radiological signs of multiply recurrent
recurrence within Wegener’s granulomatosis
2 years of follow-up of the nasal cavity. Treated
with postoperative
radiation
Chen et al. 92 Radiotherapy—92 5-year survival—59.5%, 36 had
(1996) Adjuvant chemotherapy—20 10-year survival—56.2% immunohistochemical
XRT dose 30–75 Gy to primary; studies. 69% T cell
30–64 Gy to neck phenotype; 17% B cell
lineage. Authors
recommend 45–50 Gy
Marsot- 13 – – CT and MRI useful in
Dupuch imaging. 8 of 13 patients
et al. (1992) proven to have T cell
lymphoma, 2 had Crohn’s
disease, 2 had granulomas
Ruey-Bin 1 54 Gy Co60 Rapid resolution and no Discussion of the
et al. (1988) disease 4 years later management when
etiology is unknown
Smalley 34 33/34 radiation therapy. Median 94% nasal obstruction Minimum dose 4200 r
et al. (1988) age 44 years; 24 males, 10 12 relapse lymph nodes + 4000–
females 3 diffuse histiocytic 5000 rad. Marginal failure
lymphoma 20%. Use larger volumes
67% NED 5 years
62% NED 10 years
43% NED 20 years
33% in-field failure
Muniain 2 4000 rads to nose/facial Stabilization of facial Authors concluded that in
et al. (1986) lesions patients with Wegener’s
granulomatosis who did
not respond to
cyclophosphamide, they
may respond to XRT
Polico et al. 1 Chemotherapy Chemotherapy—80%
(1986) (cyclophosphamide and regression but rapid
prednisone) radiotherapy progression
60 Gy—complete
response
Robinson 1 Paranasal 5 mm nose, palate. Age Regression of lesion Important to differentiate
et al. (1984) 39 years 60 Gy irradiation from Wegener’s
granulomatosis
Halperin 2 Upper aerodigestive passages. 1 patient did well and Disease also called lethal
et al. (1982) Ages 27 and 29 years; 45 Gy had no disease midline granuloma
cobalt irradiation 2–1/2 years’ follow-up.
The second patient
developed lesions
outside of irradiated area
and died
DeRemee 40 Nasal cavity nasopharynx palate. 3 of 20 living free of 4 patients developed large
et al. (1980) Ages: 15–80 years (average 45) disease 1–1/2–19 years cell lymphoma
The 120 patients with disease after therapy
isolated to upper respiratory tract
received radiotherapy
(continued)
(continued)
Total # of
1 2000 rads, 2-week break, Lung re-expanded Radiation of Wegner’s
additional 2000 rads to the following radiation granulomatosis lesions
trachea and bronchi led to the resolution of
signs of inflammation in
the bronchus and of
atelectasis that had
persisted despite prior
prednisone and
cyclophosphamide
treatments
Fauci 11 Radiotherapy: 8/10 apparent complete Disease activity was
(1976) 4000–5000 rad (tissue remission 2/10 initial limited to the upper
dose)/5 weeks Co60 or 2 MeV brief remission airway in all patients.
Wide-field irradiation There was no evidence of
encompassing the nasal and disseminated disease in
palatal areas and the accessory any patient
sinuses
Harrison 14 1. Deep X-ray therapy (3 Cites three cases of
(1974) patients) patients with malignant
2. Corticosteroid (3 patients) granuloma who
3. Deep X-ray therapy plus developed malignant
corticosteroid (3 patients) lymphoma and 11
4. Deep X-ray therapy plus patients with Wegener’s
intra-arterial methotrexate (1 granulomatosis
patient)
5. Intra-arterial methotrexate (2
patients)
6. Azathioprine,
cyclophosphamide,
corticosteroid. Radiotherapy
dosage varied from 800 to
1000 rad/6 days to a full curative
dose of Co60
Friedmann 5 1. Irradiation (3) 1. 2/3 alive at 8 years These cases were taken
(1971) 2. Steroids (1) and 14 years from the ENT Tumor
3. Steroids plus irradiation (1) 1/3 dead at 12 years Registry
2. Dead at 2 years
3. Dead at 6 years
Kassel et al. 1 Corticosteroid followed by oral Short-term response to Authors also report on a
(1969) methotrexate and radiotherapy, the first X-ray treatment case of Wegener’s
1000 r/6 days (2 MeV). Steroid Patient died of disease at granulomatosis
therapy was continued. 2.5 months following
Approximately 3 months later, he second treatment
received another course of
radiotherapy, 1000 r/4 days
(250 kV)
Friedmann 15 Deep X-ray therapy 6/15 survived from 8 to
(1964) 15 years
Feder et al. 4 1. Massive antibiotics (patient 1. Favorable response 1 patient has been
(1963) was acutely ill) followed later by lasted for 3 months. observed for less than
prednisolone (1 patient) Patient expired from 1 year. 1 patient died of
2. Radiotherapy 450 r/1 month (1 disease disease (this was the
patient) or 900– 2. 2 patients well at patient who received
975 r/2.5–3 months (1 patient) or 2.5–4-year follow-up 2550 r)
2550 r/3.5 months (1 patient), (one later died of
300 kV, 0.75 mm Cu filtration coronary occlusion)
HVL 1.9 mm Cu, FSD 70 cm
(continued)
Total # of
Merrill 1 Radiotherapy, 1100 r Painless swelling in right
(1961) (air)/15 days, 250 kV, to the mass parotid gland. Original
dx of chronic parotitis.
After radiotherapy, the
size of the mass
decreased and it was no
longer detectable. Nine
months later, the patient
had granulomatous
lesions of the lateral
pharynx, mucosal
hypertrophy, and
superficial ulceration of
the aryepiglottic folds.
She had been receiving
prednisone and was now
given a further course of
radiotherapy. The
patient’s symptoms
subsided. Patient died
2 months later of
respiratory obstruction
Glass 4 Radiotherapy, Good response to
(1955) 400–1200 r/5–8 weeks radiotherapy in all 4
cases
Ellis (1955) 1 Radiotherapy, 300 r/1 month Margins of the ulcer
became clean. Mucosal
junction between the
oral and nasal surfaces
of the palate healed. No
further evidence of
activity
Blizzard RM, Hung W, Chandler RW, Aceto T, Kyle M,

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Dermatologic Conditions
Khalil Sultanem
Contents 1 Keloids
1 Keloids 55
Keloids and hypertrophic scars are pathological
2 Bowen’s Disease 57
scars that arise from skin trauma such as acne,
3 Erythroplasia of Queyrat 58 folliculitis, and piercing or surgical incisions
References 59 (Betarbet and Blalock 2020). Keloids appear in
about 10% of wounds and are more common in
people with positive family history or dark skin
phototypes (Guix et al. 2008). Beside the cos-
metic impact, keloid can be responsible for pain,
pruritis, or recurrent infections. The pathophysi-
ology of keloid formation is poorly understood
but thought to be related to overproduction of
collagen fibers due to the activity of fibroblasts in
the reticular dermis in response to overexpression
of proinflammatory factors (Ogawa 2017).
Keloids are usually addressed surgically
although other options have been described,
including cryotherapy and laser ablation (Ojeh
et al. 2020). Excision alone carries a high risk of
relapse (Niessen et al. 1999). Variable adjuvant
approaches to surgical resection have been
reported in order to minimize the risk of relapse;
this includes silicone dressing, intralesional ste-
roid injections, intralesional 5-FU injections, or
topical imiquimod (Ojeh et al. 2020).
Radiation therapy was introduced as a poten-
tial treatment for keloids in 1906 (De Bearman
and Gourgerot 1906).
Radiation is rarely used as monotherapy and
more frequently as adjuvant to surgical resection
K. Sultanem (*) (Mankowski et al. 2017). Radiation has been
Department of Radiation Oncology, Jewish General approved as the most efficacious modality by the
Hospital/McGill University, Montreal, QC, Canada
e-mail: khalil.sultanem@mcgill.ca International Advisory Panel on Scar

56 K. Sultanem
Management (Mustoe et al. 2002). It acts by sup- dyspigmentation and telangiectasia. Speranza
pressing fibroblast activity to decrease collagen et al. (2007) reported on the long-term outcome
formation; it also has anti-inflammatory and anti- of orthovoltage radiation using 15 Gy in three
angiogenic properties that prevent keloid pro- fractions. They found that 60% of patients had a
gression (Lee and Jang 2018). high level of satisfaction with the cosmetic
Multiple retrospective reviews and institu- outcome.
tional experience using different techniques and The risk of radiation-related malignancies in
dose fractionation are available in the literature the surrounding tissues is low, but patients must
(Mankowski et al. 2017). It is commonly agreed be counseled about the risk before proceeding
that for radiation to be effective, it should be with therapy. A review of literature done by
delivered within 24–48 h of surgery. Ogawa et al. revealed only five reported cases of
Acute toxicity of radiation for keloids is lim- possible radiotherapy-induced malignancies
ited to erythema seen in about 14% of cases (fibrosarcoma, basal cell carcinoma, thyroid can-
(Mankowski et al. 2017). Late toxicity includes cer, and breast cancer) (Ogawa et al. 2009).
Author/year Details Dose/fractionation Results Notes

Ogawa et al. (2019) 121 patients 10–20 Gy/2–4 Fx 90% control Body site-customized
Electron rate dose fractionation
regimens
Jiang et al. (2018) 29 patients with 37 18 Gy/3 Fx 3 failures
keloids HDBT prescribed at
5 mm
Vila Capel et al. 19 patients with 20 15 Gy/3 Fx 76% control
(2013) keloids Electron rate
Kuribayashi et al. 21 patients with 36 15–20 Gy/3–4 Fx 9.7% failure 5 mm spacer used,
(2011) keloids Plesiotherapy rate prescribed at 2 mm
depth
Recalcati et al. 60 patients with 76 10–45 Gy/weekly 5 Gy 13.2% failure
(2011) keloids fractions rate
Orthovoltage
Yamawaki et al. 91 patients 16–20 Gy/4–5 Fx 56% complete
(2011) Electron response, 89%
good cosmetic
results
Viani et al. (2009) 612 patients with 892 20 Gy/10 Fx 87.6% control Excellent cosmesis in
keloids SR-90 plesiotherapy rate 70.6%
Rio et al. (2009) 58 patients with 73 20–40 Gy LDBT Ir-192 86% control
keloids rate
Narakula and 31 patients with 46 12 Gy/3 Fx 5 failures
Shenoy (2008) keloids Orthovoltage
Speranza et al. 96 patients with 102 15 Gy/3 Fx 15% failure rate 60% long-term
(2007) keloids Orthovoltage dyspigmentation
Van De Kar et al. 21 patients with 32 12 Gy/3–4 Fx 71.9% failure High failure rate noted
(2007) keloids Orthovoltage rate
Veen and Kal 35 patients with 54 14–18 Gy/3 Fx every 5 failures Better outcome with
(2007) keloids 6h higher dose
HDBT 18Gy/3 Fx
Emad et al. (2005) 19 patients with 44 12 Gy/3 Fx 70.4% 89.5% satisfaction
keloids Orthovoltage complete 17% dyspigmentation
remission
Garg et al. (2004) 12 patients with 17 15 Gy/3 Fx 88% control
keloids, recurrent Iridium HDBT rate
post-initial excision, prescribed at 1 cm
and adjuvant EBRT
Dermatologic Conditions 57
(continued)
Ragoowansi et al. 80 patients 10 Gy/1 Fx 16% failure rate
(2003)
Guix et al. (2001) 169 patients (22 12–18 Gy/4–6 Fx over 4.7% failure Hyperpigmentation in
patients without 2 days rate 10 patients,
surgical resection) Iridium HDBT telangiectasia in 12
prescribed at 1 cm patients
Wagner et al. (2000) 139 patients with 166 7.5–28.5 Gy/1.5–3 Gy 80% control
keloids per Fx rate
SR-90 plesiotherapy
HDBT high-dose-rate brachytherapy, LDBT low-dose-rate brachytherapy
2 Bowen’s Disease (large lesion, cosmetically or functionally sensi-

tive regions) (Vanderspek et al. 2005).
Bowen’s disease or cutaneous squamous cell Radiotherapy is best suited to treat perianal
carcinoma in situ was first described in 1912 and genital Bowen’s disease with good outcome
(Vanderspek et al. 2005). It usually presents as and little toxicity (Papillon and Chassard 1992),
an erythematous scaly well-demarcated lesion while caution should be used treating lower
on the extremity, head and neck region, or gen- extremities with radiation due to poor healing
italia; it is more common in the elderly (Dupree et al. 2001).
(Mohandas et al. 2020). Bowen’s disease is Techniques of radiation used to provide super-
usually indolent with a low risk of progressing ficial coverage varied in the literature and
to invasive SCC (3–10%) (Vanderspek et al. included orthovoltage, megavoltage photon, elec-
2005). Perianal and genitalia lesions carry the tron, and plesiotherapy (Vanderspek et al. 2005;
highest risk of progression to invasive SCC Herman et al. 2008; Gandhi et al. 2014).
(Cox et al. 2007). There is no consensus as to the ideal dose and
Options of treatment described (Cox et al. fractionation regimen. VanderSpeck et al. (2005)
2007) include observation, excision, topical rem- attempted to correlate the biologically effective
edies (5-FU, imiquimod), cryotherapy, electro- dose to local control and toxicity by analyzing their
cautery, photodynamic therapy, and radiotherapy. data and apply an alpha over beta of 10 for local
There is little data comparing options of ther- control and 3 for late toxicity. In their study, BED
apy, especially when it comes to radiation (Bath- did note correlate with local control with excellent
Hextall et al. 2013). control rate over all dose fractionation regimen
Radiation is rarely used as a treatment modal- (overall local control rate of 93%); high dose per
ity but can be advantageous in patients who fractions (>4 Gy) was associated with higher late
refuse surgery or if surgery is not recommended toxicity especially in lower extremities.

Herman et al. (2008) 14 lesions of the 25–60 Gy/2–3 Gy per 100% control
fingers Fx rate
Photon using water bath
Vanderspek et al. 44 patients 10–52 Gy/1–15 Fx 93% local 3 cases of
(2005) Orthovoltage control rate nonhealing ulcer
(dose per fraction
>4 Gy)
Dupree et al. (2001) 11 patients and 16 44–51 Gy/2.5–3.5 Gy 100% control High rate of
lesions per fraction rate residual benign
Orthovoltage ulcer in lower
extremities
(continued)
58 K. Sultanem
(continued)
Chung et al. (2000) 8 patients and 29 35 Gy using a 100% control
lesions holmium-166 skin patch rate
Caccialanza et al. 62 patients Variable doses/ 1 failure
(1999) fractionations
Orthovoltage
Cox and Dyson (1995) 59 patients with 12–18 Gy/1–2 weekly 100% control 33% nonhealed
lower extremities fractions rate ulcers
lesions Orthovoltage
Blank and Schnyder 73 patients Soft X-ray 100% control
(1985) 32–50 Gy rate in
extragenital
88% control
rate in
anogenital
3 Erythroplasia of Queyrat apy, and topical cytotoxic agents (5-FU,

imiquimod).
Erythroplasia of Queyrat is a squamous cell Radiotherapy is an option of treatment in
carcinoma in situ located on the glans penis or recurrent or hard-to-manage cases. The use of
prepuce. It accounts for roughly 10% of all radiation for erythroplasia of Queyrat should be
penile malignancies and may lead to invasive considered carefully and only when other options
squamous cell carcinoma. Standard therapy of therapy have been exhausted. Care should be
includes local excision, partial or total penec- taken to preserve sexual and urinary function and
tomy, cryotherapy, photodynamic or laser ther- sensation.

Caccialanza and 5 Soft X-ray, 5 Gy twice a 100% complete response 80.4-month mean
Piccinno (2000) patients week to ~50 Gy without recurrence follow-up
Acceptable cosmetic results in
4/5
Blank and 4 Soft X-ray 1 failure
Schnyder (1985) patients 32–50 Gy
Graham and 4 Details not published 3 failures
Helwig (1973) patients
Kaplan and 1 6600–6900 Gamma-r using Complete resolution Penile glans edema
Katoh (1973) patient a Ra-226 mold requiring a dorsal
slit
Mantell and 1 Yttrium-90 applicator Complete resolution
Morgan (1969) patient Surface dose of
1500 r/10 min
Brown (1966) 1 300 r delivered in 1 course Symptomatic relief but relapse
patient with kilovoltage X-ray treated with steroids and then
therapy excision
Dermatologic Conditions 59
References Guix B, Andres A, Salort P (2008) Keloid and hypertro-

phic scars. Springer
Herman JM, Pierce LJ, Sandler HM, Johnson TM (2008)
Bath-Hextall FJ, Matin RN, Wilkinson D, Leonardi-
Radiotherapy using a water bath in the treatment
Bee J (2013) Interventions for cutaneous Bowen’s
of Bowen’s disease of the digit. Radiother Oncol
disease (review). Cochrane Database Syst Rev
88:398–402
2013(6):CD007281
Jiang P, Geenen M, Siebert F, Druecke D (2018) Efficacy
Betarbet U, Blalock TW (2020) Keloids: a review of
and the toxicity of the interstitial high-dose-rate
etiology, prevention, and treatment. J Clin Aesthet
brachytherapy in the management of recurrent keloids:
Dermatol 13:33–43
5-year outcome. Brachytherapy 17:597–600
Blank A, Schnyder U (1985) Soft-X-Ray therapy in
Kaplan C, Katoh A (1973) Erythroplasia of Queyrat
Bowen’s disease and erythroplasia of Queyrat.
(Bowen’s disease of the glans penis). J Surg Oncol
Dermatologica 171:89–94
5:281–290
Brown P (1966) Erythroplasia of Queyrat. Br J Plast Srug
Kuribayashi S, Miyashita T, Azawa Y, Kumita S (2011)
19:378–382
Post-keloidectomy irradiation using high-dose-rate
Caccialanza M, Piccinno R, Beretta M, Gnecchi L (1999)
superficial brachytherapy. J Radiat Res 52:365–368
Results and side effects of dermatologic radiotherapy:
Lee HJ, Jang YJ (2018) Recent understandings of biology,
a retrospective study of irradiated cutaneous epithelial
prophylaxis and treatment strategies for hypertrophic
neoplasms. J Am Acad Dermatol 41:589–594
scars and keloids. Int J Mol Sci 19(711):1–19
Caccialanza M, Piccinno R (2000) Radiotherapy of eryth-
Mankowski P, Kanevsky J, Tomlinson J, Dyachenko A,
roplasia of Queyrat. Skin Cancer 15:201–206
Luc M (2017) Optimizing radiotherapy for keloids:
Chung YL, Lee JD, Band D, Lee M (2000) Treatment of
a meta-analysis systematic review comparing recur-
Bowen’s disease with specially designed radioactive
rence rates between different radiation modalities.
skin patch. Eur J Nucl Med 27:842–846
Ann Plast Surg 78:403–411
Cox N, Dyson P (1995) Wound healing on the lower leg
Mantell B, Morgan W (1969) Queyrat’s erythroplasia
after radiotherapy or cryotherapy of Bowen’s disease
of the penis treated by beta particle irradiation. Br J
and other malignant skin lesions. Br J Dermatol
Radiol 42:855–857
133:60–65
Mohandas P, Lowden M, Varma S (2020) Bowen’s dis-
Cox NH, Eedy DJ, Morton CA (2007) Guidelines for
ease. Br Med J 368:m813
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Mustoe TA, Cooter RD, Gold MH, Ziegler UE (2002)
International advisory panel on scar management:
De Bearman R, Gourgerot H (1906) Cheloides des
international clinical recommendations on scar man-
Maqueuses. Ann Dermatol Syphilol 7:151
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Dupree MT, Kiteley RA, Weismantle K, Johnstone PA
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(2001) Radiation therapy for Bowen’s disease: les-
cal review of multi model approach for treating ear
sons for lesions of the lower extremity. J Am Acad
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Niessen FB, Spauwen PH, Schalkwijk J, Kon M (1999)
Emad M, Omidvari S, Dastgheib L, Ghaem H (2005)
On the nature of hypertrophic scars and keloids: a
Surgical excision and immediate postoperative radio-
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in the management of keloids: a prospective clinical
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60 K. Sultanem
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J Radiat Oncol Biol Phys 63:505–510
Infectious Disease
David Roberge
Contents Prior to the availability of antibiotics and anti-

1 Acne 62 virals, radiotherapy was used in the treatment of
1.1 Acne Radiotherapy 62 a wide range of infections (Berk and Hodes
2 Carbuncles and Furuncles 63
1991). Only selected indications are covered in
2.1 Furuncle Radiotherapy 63 this chapter. Despite the many subjective reports
2.2 Carbuncle Radiotherapy 64 of clinical benefit and the large number of patients
2.3 Combined Reports of Furuncle and treated, the clinical evidence of efficacy remains
Carbuncle Radiotherapy 64
generally weak. That said, there is some labora-
3 Fungal Infections/Tinea Capitis 65 tory evidence to support that the effects may be
3.1 Hemoptysis Related to Aspergilloma 65
real (Goldberg et al. 1935). The mechanism of
3.2 Tinea Capitis 66
action remains unclear but is not likely to be by
4 Gas Gangrene 67 direct action on what are typically relatively
5 Herpes Zoster 68 radiation-resistant pathogens. With more effec-
5.1 Herpes Zoster Radiotherapy 68 tive alternative treatments and considering the
6 Ocular Trichiasis 69 potential carcinogenic effects of radiation, there
7 Scalp Folliculitis 69
is now limited interest in radiotherapy for infec-
7.1 Perifolliculitis Capitis Abscedens et tions. In the context of the SARS-CoV-2 pan-
Suffodiens 70 demic, there has been a small wave of renewed
7.2 Folliculitis Decalvans 71 interest, which is already waning as this section
8 SARS-CoV-2 71 is written.
9 Tuberculosis 72 Although there are no mainstream indications
for radiotherapy in the contemporary manage-
10 Warts and Condylomas 72
10.1 Warts 73
ment of infection, there may be specific cases
10.2 Anogenital Warts/Condyloma 73 where the potential benefit can be felt to out-
weigh the risks.
References 74
D. Roberge (*)
Department of Radiation Oncology, Centre
Hospitalier de l’Université de Montréal,
e-mail: david.roberge.med@ssss.gouv.qc.ca

Published Online: 03 December 2022
62 D. Roberge
1 Acne oral therapeutics. Although the psychological

and physical scars of this disease are real, a
Roentgen therapy of acne has been reported as generally self-resolving disease of youth is ill-
far back as 1897. Historically, acne, particu- suited to treatments with potentially carcino-
larly the more severe forms, was treated by and genic ionizing radiation. Thyroid cancer,
was reported to respond to fractionated ortho- salivary gland tumors, as well as breast cancers
voltage radiation. In a national survey of have been reported as consequences of acne
American dermatologists collecting data in radiotherapy. Doses used varied and lead to a
1957–1958, radiation had occurred in 26% of thyroid cancer risk of 1:16 to 1:12,000 for chil-
clinic visits for acne (Welton and Greenberg dren exposed to 10 Gy to the chin. Other thy-
1963; Welton 1960). Any positive effect of radi- roid abnormalities are seen with a frequency of
ation was not likely to have been predominantly 2–3% at an interval ranging from 9 to more
antibacterial. Use subsequently plummeted. than 40 years (Albright 1967; De Jong et al.
Current treatment is tailored to the severity of 1991; Goldschmidt et al. 1983; Paloyan and
the disease and includes a variety of topical and Lawrence 1978; Thomson et al. 1984).
1.1 Acne Radiotherapy

Total #
of
De Groot 40 300 r Grenz rays 3 At 2–6 weeks, of 29 patients Although intended to be
et al. times a week to 1600 r undergoing hemifacial irradiation and blinded, this was often
(1963) to a randomly selected seen in follow-up, in 14 there was no illusory given the
side of the face difference between right and left, in erythema and
14 the irradiated side was better, and pigmentation caused by
in 1 the irradiation side was worse. At the treatment
8–14 weeks, there was no longer any
difference
Way 451 Unspecified 32% good or excellent results in 451
(1960) patients treated with radiation, 38% in
those treated without
Baer et al. 259 85 r per fraction, 89% “cured” (vs. 79% in those treated Suggestion of a dose
(1952) typically to less than without radiation) response with better
1000 r but >2000 r in 3 results above 1000 r
patients
Crawford 58 60–75 r on each side of 35 no residual acne Represents a subset of
et al. the face (with or 19 occasional lesions 129, which could be
(1951) without an additional 3 had improvement, but with contacted for follow-up.
central face dose of unsatisfactory result All followed up for
15 r) weekly until 1 no improvement ≥5 years. 9 patients had
clearing, for a total of telangiectasia
500–1450 r
Infectious Disease 63
Total #
of
Quastler 60 Three successive The conclusion was that the ideal
(1950) experiments used a regimen was 4 small doses (25–30 r)
factorial design given at short intervals (3 times per
The first tested dose week) and that higher doses did not
(60–120 r per week), produce better results
timing (1, 1.4, 2
fractions per week), and
radiation quality
The second tested lower
doses (10–20–30 r per
fraction) at shorter
intervals (2, 3, or 6 per
week)
The third tested
Kline and 50 Sham radiation to the 13 lost to follow-up
Gahan left cheek 1 did not have acne
(1942) Weekly fractions of 1 stopped for toxicity
75 R to the right cheek 20 improved on both sides
(average of 10) 9 improved on treated side
6 had no improvement
Niles 40 Sham radiation to the 23 both sides equally improved
(1933) left cheek 14 right better than left
7–16 fractions of 70 R 2 left side improved more than the
to the right cheek right
1 neither side improved
2 Carbuncles and Furuncles radiation was thought to be useful in their treat-

ment (Berk and Hodes 1991; Carp 1927;
Furuncles (boils) are isolated infections of sweat Calabrese 2013). It is unclear what benefit was
glands or hair follicles which, when they derived from these radiation treatments. Selected
coalesce, become carbuncles. These infections references are provided for historical interest;
have a predilection for the back of the neck, face, such treatments are no longer used in modern
axillae, and buttocks. In the pre-antibiotic era, practice.
2.1 Furuncle Radiotherapy

Total # of
Whitmore 151 ½–1 ESD which 3% not improved “The most striking result of the treatment has
(1935) could be repeated 75% improved been the relief of pain, and if the treatment
after a week 22% aborted accomplished nothing more, it would be justified
34% for this alone”
spontaneous
drainage
Baensch 103 150–250 r 1.9% mortality Facial furuncles
(1933) 94% rapid or
accelerated
healing
ESD erythema skin dose
64 D. Roberge
2.2 Carbuncle Radiotherapy

Total # of
O’Brien 130 Average of 3 fractions 3% mortality Shorter hospital stay in
(1939) of medium/high- those managed with
voltage filtered X-rays radiotherapy alone (without
surgery)
King (1937) 39 (33 with 175–350 R which 8% complete failure Even in those patients
follow-up) could be repeated 76% rapid improvement without shortening of
course of their disease, pain
relief was common
Whitmore 19 ½–1 ESD which could 5% not improved
(1935) be repeated after a 85% improved
week 10% aborted
37% spontaneous drainage
Light and 50 30–50% ESD 69% helpful
Sosman
(1930)
Carp (1927) 28 0.66–0.75 SED 50% successful “There has been no proof in
(Calabrese 2013) 46% unsuccessful the clinical cases analyzed
4% died in this series that X-ray
therapy alone effected a
cure”
Hodges 26 4 mA, 9″ spark gap, 92% marked benefit
(1925) 8 min, 9 mm Al, 9″
distance (could be
repeated at half dose
once or twice)
Lewis 16 2/3 ESD 88% healed without surgery
(1923) 83% pain relief
Dunham 67 Single fraction of >10 Pain relief is described after “Nothing in all roentgen
(1916) Kienböck units 24 h with frequent therapy gives such positive
subsequent formation of an and uniformly perfect
abscess, which heals after results as the treatment of a
being lanced carbuncle”
ESD erythema skin dose
2.3 Combined Reports of Furuncle and Carbuncle Radiotherapy

Total # of
Morton and 100 175–350 R which 93% pain relief Results were better (64% aborted vs. 0%)
Leddy (1930) could be repeated 28% aborted when treatment was given within 72 h of
18% prompt onset
improvement
44% slow
improvement
10% failure
3 Fungal Infections/Tinea low-up of 26 years, there was an absolute increase

Capitis in mortality as compared to siblings and other
unirradiated controls. This increase in mortality
The most widespread use of radiotherapy in the was attributable to a range of fatal malignancies:
management of fungal infections was related to leukemia (RR 2.3), ENT tumors (RR 3), sarco-
tinea capitis. Radiotherapy was used to cause mas (RR 9), and central nervous system tumors
durable but reversible alopecia (Lydon et al. 1949). (RR 1.5).
Doses used for epilation were 300–600 R. These Other applications of radiotherapy for superfi-
treatments were abandoned in the late 1950s with cial or deep fungal infections have also been ren-
the advent of antifungal medications. dered obsolete by antifungal agents.
Unfortunately, large numbers of young patients Contemporary advocacy for irradiation fungal
were treated before the long-term risks were fully infections is rare (Gupta et al. 2021). If there is a
understood. In Israel alone, nearly 20,000 children current indication, it may be in the management
were irradiated between 1948 and 1960. of refractory hemoptysis from aspergillosis.
In a series of 2200 children followed for up to Despite the paucity of clinical reports, a 2020
40 years, there was a 20% incidence of skin can- review of this condition placed radiotherapy in
cers; the minimal latency period seemed to be their algorithm for cases of serious acute hemop-
20 years. In a large cohort of 10,832 children irra- tysis refractory to embolization (Lang et al.
diated for tinea with a subsequent average fol- 2020).
3.1 Hemoptysis Related to Aspergilloma

Total #
of
Sapienza 21 20 Gy in 10 daily fractions 20/21 had initial relief of All patients had a
et al. (2015) (with potential retreatment to hemoptysis with 20 Gy. At history of treated
another 14–20 Gy) median follow-up of 25 months, pulmonary
4 local recurrences including 2 tuberculosis
deaths from hemoptysis
Samuelian 1 28 Gy in 8 weekly fractions Gradual resolution of the The intent was to give
et al. (2011) hemoptysis with complete 3.5 Gy weekly
resolution at 8 weeks and fractions for 1 week
continued benefit at 2 years past resolution
Glover et al. 1 8 Gy in 2 fractions 10 days Resolution of the hemoptysis Aspergilloma in the
(2007) apart background of
p-ANCA-positive
vasculitis
Falkson 5 7–14 Gy in weekly fractions Bleeding was controlled in all
et al. (2002) of 3.5 Gy patients
Shneerson 1 20 Gy in 5 fractions through Cessation of bleeding during the
et al. (1980) a direct Co60 field with an 8-month follow-up period
additional course of 10 Gy in
5 through opposed field
8 weeks later
66 D. Roberge
3.2 Tinea Capitis

Author, year Cases Site, age Treatment Results Comments
Rubinstein 201 Scalp; X-ray doses <850 r 43/201(21.4%) with Patients were all
et al. 25–63 years, with brain doses intracranial Jewish/latent period
(1984) with a mean of ranging from 70 to meningioma had 38 years. Data
45 years (at the 175 r. Some patients previously received compared with
time of received more than a X-ray for tinea capitis patients with
meningioma) single treatment meningioma without
X-ray exposure
Shore et al. 2226 Scalp; median 300–380 r to 5 80 basal cell Minimum latent
(1984) age 7.9 years overlapping fields on carcinomas of the scalp period was 20 years
the scalp to cause or face have occurred Skin cancers were
depilation among 41 irradiated most prevalent in
This delivered doses children Caucasians and on
of 300–600 r to The cumulative the face where there
various portions of incidence of skin cancer was additional UVR
scalp, lower doses to 35 years postirradiation exposure. Data
face and neck was 4.9 per 100 obtained via
persons. The risk questionnaire and
increased with time compared with
nonirradiated
controls
Soffer 42 Scalp; 45 years Patients previously Patients had statistically Data were compared
et al. (at the time of had scalp irradiation significant higher to patients with
(1983) meningioma for tinea capitis number of calvarial meningiomas,
occurrence) tumors (p < 0.001) without prior history
Multiple meningioma, of X-ray
with high recurrence
(p < 0.02)
Histologically
malignant (p < 0.01)
Ron et al. 10,842 Scalp; mean Mean brain dose of Irradiated children had Data compared to
(1982) age 7.1 years 130 r from X-ray poorer scholastic ethnic-, sex-, and
treatment for tinea aptitude, IQ, age-matched people
capitis psychologic tests; from the general
75 kV X-ray machine completed fewer school population and to
grades; had an siblings
increased risk for
mental hospital
admissions; slightly
higher frequency of
mental retardation
Yaar et al. 44 Scalp Cortex doses of Increased abnormalities Treatment
(1982) 121–139 r in EEG power values administered
2.5 cm compared to controls, 20 years previously
deeper—95–121 r suggesting permanent
when scalp treatment changes in EEG activity
was given
Ron and 10,842 Scalp Thyroid dose 9 r An excess risk of 8.3 Data compared to
Modan when scalp X-ray cases/year/r/million matched controls.
(1980) given population of benign Children irradiated
and malignant thyroid under age 6 had the
neoplasms among highest risk for
persons given X-ray for developing
tinea capitis carcinoma
Author, year Cases Site, age Treatment Results Comments

Yaar et al. 10,842 Scalp ages Cortical doses Significant radiation Data compared to
(1980) 3–13 years, 121–139 r when scalp effects were seen in nontinea,
average age treatment given visual evoked responses nonirradiated
7 years in adults irradiated as matched controls
children
Pousti 7 Scalp; Scalp X-ray for tinea All developed Intervals of
(1979) childhood capitis to achieve malignant tumors of the 18–50 years
epilation scalp
5 basal cell carcinoma,
2 squamous cell
carcinoma
Spallone 2 Scalp; infancy Scalp X-ray for tinea Both developed Latency period of
et al. and 5 years capitis meningioma 25–45 years
(1979)
Omran 177 Scalp; average Scalp X-ray for tinea Irradiated group had X-ray treatment
et al. age 7.8 years capitis more psychiatric 10–29 years earlier
(1978) symptoms and
abnormal MMPI
(Minnesota Multiphasic
Personality Inventory)
scores, and more
psychiatric disorders
Modan 10,902 Scalp; ages Scalp X-ray delivered Increased rate of Data compared to
et al. 2–10 years at thyroid dose of <9 r malignant thyroid nonirradiated sex-,
(1977) tumors of 6.3/106/year age-, and ethnic-
among irradiated matched controls,
children compared to and nonirradiated
controls matched sibling
controls
Shore et al. 2215 Scalp; Scalp X-ray, 100 kV Excess incidence in the Data compared to
(1976) childhood unfiltered X-ray, irradiated group of nonirradiated age-,
450–850 r to scalp tumors of the head and sex-, and race-
400 r to cranium neck, including skin, matched controls
70–175 r to brain 6 r brain, thyroid, and
to thyroid parotid. No excess
mortality in white
patients, a 40% excess
of treated psychiatric
disorders, but not in
blacks
tions, recovering without the need for amputa-

4 Gas Gangrene tion. This led Dr. Kelly to treat additional patients
and report his experience of such fractions deliv-
In the pre-antibiotic era, gas gangrene (clostridial ered twice daily for 2–3 days (Kelly et al. 1938).
myonecrosis) was a frequent complication of During the World War II, portable X-ray units
traumatic injury with a high mortality rate. In were used to treat open wounds prophylactically.
1928, Dr. Kelly (a radiologist) was referred a Hundreds of wounds were treated before the
comatose 21-year-old patient with gas gangrene. practice of irradiation gas gangrene was aban-
The referral was for diagnostic imaging, but see- doned. It remains unclear if there was any real
ing the poor condition of the patient and having therapeutic benefit (Calabrese and Dhawan
used radiotherapy for other infections, Dr. Kelly 2012). Today, surgery, antibiotics, and sometimes
administered a first fraction of 100 R. The patient hyperbaric oxygen are used as standard
improved and went on to receive additional frac- treatment.
68 D. Roberge
5 Herpes Zoster decrease the duration of symptoms and may

decrease the risk of postinfection neuralgia.
Historically, irradiation of herpes zoster was said There are cases where radiosurgery appears to
to be effective when the “bouquet” of lesions first have successfully used to manage postherpetic
formed over the sensory fibers. The evidence trigeminal pain, although the evidence is not as
available is insufficient to demonstrate any bene- strong as for classical trigeminal neuralgia (Keep
fit to these treatments, and such treatments are et al. 2005; Kondziolka et al. 2002; Urgosik et al.
not indicated today. Antivirals are used to 2000).
5.1 Herpes Zoster Radiotherapy

Total # of
Rhys-Lewis 139 100 r (skin dose) in 10 days to the area overlying Complete relief: No clear
(1965) affected root ganglion: 23/29 (1) evidence
1. Patients with slight symptoms 45/73 (2) that
2. Patients with moderate symptoms 13/37 (3) radiation
3. Patients with severe symptoms therapy is
of any
value
140 Controls—no treatment Complete relief
26 Ophthalmic zoster only 1000 r (skin dose) in Complete relief:
10 days to area overlying affected root ganglion: 10/10 (1)
1. Patients with slight symptoms 3/8 (2)
2. Patients with moderate symptoms 2/8 (3)
3. Patients with severe symptoms
36 1000 r (skin dose) in 10 days to the area overlying Complete relief:
affected root ganglion: 7/7 (1)
1. Patients with slight symptoms 13/21 (2)
2. Patients with moderate symptoms 3/8 (3)
3. Patients with severe symptoms
31 Ophthalmic zoster only (1, 2, 3), same as directly Complete relief: Treated
above 3/3 (1) prior to
9/13 (2) institution
5/15 (3) of controls
O’Brien 15 200 kV, 0.5 mm Cu plus 1 mm Al filtration, FSD 15/15 responded to
(1950) 50 cm irradiation
Field size:
15 × 10 cm 800 r/4 F/2 weeks to the spinal nerve
roots involved
Reeves and 56 200 kV, 0.5 mm Cu plus 1 mm Al filtration, FSD, 38/56 cured
Waters 50 cm. 800–1000 r in 4–5 fractions over 4–5 days
(1946)
McCombs 72 200 kV, 1 mm Cu plus 1 mm Al filtration, FSD, 56/72 cured 46% cured
et al. (1940) 50 cm. 6 × 15 cm portal over spinal root ganglion within
of the nerves involved. 1000–1200 r in 5–6 814 days
fractions over 5–12 days
51 Controls (14 received injections of pituitrin) 51/51 cured Only 16%
cured
within
8–14 days
Total # of
Pillsbury and 50 100 kV, no filter, FSD, 30 cm. 260–325 r in 4–5 Effective in
Fonde (1936) fractions in 10–13 days reducing the
inflammatory
reaction at the site
of the lesion, but
little effect on pain
Keichline 62 kV not given. 3 mm Al filtration, FSD, 30 cm 90% required
(1934) 148 r to the affected root ganglion—may be single dose
repeated if necessary 8% given a second
dose
2% given 3 doses at
10-day intervals
6 Ocular Trichiasis epilation, consideration has been given to using

an epilating dose of superficial irradiation. A lim-
Ingrown eyelashes (trichiasis) can complicate ited number of patients have been treated. No
many disorders of the eyelids, including infec- reports have been identified since 1984, and it
tions such as herpes zoster or trachoma. Treatment would seem unlikely that this approach would
can involve plucking, surgical excision, electrol- find contemporary use in view of the numerous
ysis, and cryotherapy. Since a goal of treatment is alternatives.
Author, year Total # of patients Treatment Results Notes

Hartzler et al. 2 4000 rad (300 rad Complete epilation An experimental study
(1984) 3×/week) 110 kV, in rabbits, and their
10 mA, TSD-20 cm, experience with 2
HVL 1.0 mm A1 patients who had
trichiasis from
pemphigus and trachoma
Lamb (1965) 63 (112 lid 500 R to eyelid, 36 patients had No complications
margins) superficial 3–5-year follow-up:
irradiation. Internal 33—permanent
contact eye shield absence of lashes,
used 3—regrowth of
lashes
7 Scalp Folliculitis condition with folliculitis and perifolliculitis

resulting from occlusion of the hair follicles and
Several conditions can present as scalp folliculi- secondary bacterial infection. The disease
tis; among them are folliculitis decalvans capil- spreads horizontally and forms sinus tracts,
litii, perifolliculitis capitis abscedens et resulting in abscess formation, alopecia, and
suffodiens, erosive pustular dermatitis, lichen scarring. Responses following scalp epilation
planopilaris, and eosinophilic pustular have been seen with temporary control of the
folliculitis. inflammatory process. Standard initial manage-
Perifolliculitis capitis abscedens et suffodiens ment can include oral antibiotics and retinoids.
(dissecting cellulitis) is an inflammatory scalp Adjunctive treatments in refractory cases can
70 D. Roberge
include steroids, incision, topical cleansers, oral agement typically begins with antibiotics and
zinc, laser, or even anti-TNF antibodies. adjunctive steroids. Treatment options for
Folliculitis decalvans is an uncommon, refractory disease are similar to those of perifol-
chronic scarring alopecia which classically liculitis capitis abscedens et suffodiens.
presents as an expanding patch of alopecia with Radiotherapy has been anecdotally used in
peripheral pustules on the scalp. Standard man- refractory cases.
7.1 Perifolliculitis Capitis Abscedens et Suffodiens

Investigator, year Cases (ages) Treatment Results Notes
Johannesson and 4 (ages 300–600 r using Complete scalp Duration of disease
Lindelöf (1985) 22–37 years) 85 kV machine with epilation and pustular prior to X-ray
1 mm A1 filter and lesions subsided epilation was
2 mm Al HVL, 10 months to
using Kienböck- 8 years. All patients
Adamson failed prior topical
technique, or with a and systemic
4 MeV linear antibiotics.
accelerator Follow-up of short
rotational treatment duration
1 of 4 cases recurred
Kumar et al. (1976) 16 (ages Grenz ray: 14/16 (87.5%) Double-blind trial.
27–71 years) 11 kV, 10 mA, complete healing on One side of scalp
HVL, 0.03 mm Al the Grenz ray-treated received active
4 Gy given on 6 scalp after 6 weeks; 9 treatment; the other
occasions at 1-week patients were still free side was treated with
intervals of lesions of scalp placebo
3 months after the
start of treatment.
Grenz rays were
significantly better
than placebo
(p < 0.0001)
McMullan and 4 (ages Epilating dose In all cases, disease In their discussion,
Zeligman (1956) 19–33 years) (365 r 80 kV refractory to the authors have
X-rays) antibiotics responded found 7 other
within 1–3 months of anecdotal reports of
radiotherapy X-ray therapy; the
first was published
in 1913 (McMullan
and Zeligman 1956;
Asbeck 1937;
Barney 1931;
Cannon 1944; Cueni
II 1928; Estrin 1948;
Ruete 1913)
7.2 Folliculitis Decalvans

Investigator, year Cases Site, age Treatment Results Notes
Elsayad et al. 1 Scalp, 5 Gy in 5 Substantial durable Refractory to 5 different
(2015) 45-year- IMRT (last follow-up at oral antibiotics, oral and
old followed by 26 months) topical glucocorticoids,
another 6 Gy symptomatic adalimumab, photodynamic
in six 4 months improvement. therapy, bleomycin
later Subtotal permanent electrochemotherapy
alopecia.
Follow-up
treatments with
laser epilation
Smith et al. 1 Scalp, Four 50 kVp Complete Refractory to 7 different
(2006) 32-year- fields for remission noted at oral and topical antibiotics,
old 440 cGy in a 6 months without steroids, retinoids, dapsone,
single fraction recurrence at chloroxine, Nizoral, oral
23 months zinc, and Nd:YAG laser
(not tolerated)
8 SARS-CoV-2 included the use of SARS-directed monoclonal

antibodies, antivirals, antibodies to IL-6, and
The period during which much of this textbook dexamethasone. A component of COVID-19 is
was written was marked by a worldwide pan- an inflammatory phase in which radiotherapy has
demic related to the SARS-CoV-2 coronavirus been considered a potential therapeutic.
and the COVID-19 disease it causes. With mil- Unconvincing reports are available for treatment
lions deceased and manyfold more hospitalized, of a small number of patients. Results of larger
there has been a race to develop therapeutics for trials and reporting of higher level evidence are
SARS-CoV-2. Guidelines are evolving but have so far lacking.
Investigator, year Cases Treatment Results Notes

Arenas et al. (2021) 36 (mean age 84) 0.5 Gy whole 13 patients died, 8 Although a second
lung due to COVID-19 0.5 Gy dose was
allowed, it was not
administered in any
patient. Eligible
patients were “not
eligible” for intensive
care due to
comorbidities or
performance status
Sharma et al. (2021) 10 (median age 51) 70 cGy whole 90% “response rate” Eligible patients were
lung generally
hospitalized with
moderate-to-severe
infection (ventilated
patients were
excluded)
72 D. Roberge
Investigator, year Cases Treatment Results Notes

Ganesan et al. (2021) 25 (mean age 57) 0.5 Gy whole 2/3 reduction in Eligible patients were
lung oxygen requirement hospitalized with
at 48 h. 12% respiratory frequency
mortality at day 14 24/min, oxygen
saturation on room
air <94% and SpO2/
FiO2 ratio >89 and
<357
Hess et al. (2021) 10 (age 43–104) 1.5 Gy whole Compared to Eligible patients were
lung matched controls, hospitalized and
shorter time to required
recovery (3 vs. supplemental oxygen
12 days) 3 patients having
progressed prior to
treatment were
excluded from the
analysis
Ameri et al. (2021) 10 (age 60–87) 0.5–1 Gy whole 5 patients discharged Eligible patients were
lung from hospital, 1 ≥60 years of age
opted out, 4 died with SpO2 ≤93% or
respiratory rate ≥30/
min
Sanmamed et al. (2021) 9 (age 57–77) 0.1 Gy whole No statistically Eligible patients were
lung significant change in ≥50 years of age and
primary outcome required
(CT imaging). 2 supplemental oxygen
patients died, 7 were
discharged
Papachristofilou et al. 11 (22 patients 1 Gy to dmax Significant reduction Eligible patients
(2021) randomized 1:1 to with 10 MV in lymphocyte count, required mechanical
RT or sham-RT) photons otherwise no ventilation. Treated
(estimated mean difference in patients were aged
lung dose 0.8 Gy) ventilator-free days, 54–84
overall survival,
oxygenation, or
inflammatory
markers
Moreno-Olmedo et al. 2 (age 65 and 80) 0.8 Gy whole Rapid respiratory
(2021) lung improvement in both
patients
9 Tuberculosis 10 Warts and Condylomas
As with other inflammatory conditions, tubercu- Warts are manifestations of infection by various
losis lymphadenitis responded to superficial strains of human papillomavirus. Lesions may
X-rays. The availability of modern antibiotics regress spontaneously, but more refractory dis-
obviates the need for X-ray treatment of tubercu- ease may be associated with immune suppres-
losis (Aceto et al. 1953; Lampe et al. 1949; sion. Large locally invasive (but histologically
Bertram 1948; Kelley 1948; Siddique 1947; benign) lesions of the anogenital region have
Amundsen 1925; Wetterstrand 1925; McIntosh been termed “Buschke–Löwenstein” tumors
1944). (Armstrong et al. 2009)—these exist on a spec-
trum with verrucous carcinomas and squamous There may remain selected cases where radio-
cell carcinoma. Cryotherapy and salicylic acid therapy may have a role, notably if the life expec-
represent first-line management of warts, while tancy of the patient is otherwise limited or when
refractory lesions may be addressed with topical extensive surgery would be required (Danoff
immunotherapy or local antineoplastics. A wider et al. 1981). This is illustrated in a report from a
range of destructive methods are applied to ano- Perth radiotherapy unit, in which six patients
genital condylomas as well as cytodestructive were irradiated for warts in the 3-year period of
and immune therapies. The use of radiation to 1999–2001 (Thom et al. 2003).
treat warts has been in practice since the 1900s.
10.1 Warts
Author, year Total # of patients Method Results Comments
Thom et al. 6 patients, 10 20 Gy in 2 Not reported With 6 patients over
(2003) warts fractions or 15 Gy 3 years, the second most
in 3 (over common benign lesion
2 weeks) treated with superficial
HVL 3–10 mm Al X-rays
Veien et al. 1122 patients, 3000 r, 29 kv, 95% satisfactory Sequelae: hyperkeratosis,
(1982) 3675 warts 3 mm Al 4.8% sequelae atrophy with
(See comments) telangiectasia, erythema.
No malignant
transformation. 5–22-year
follow-up. Warts 6 mm or
less treated. Not to avoid
the arch of foot, dorsal
aspects of hands and
fingers
Shair et al. 350 patients, 483 100 kV, 0.5 mm 91% good result 3–28-year follow-up
(1978) warts Al 97% hyperkeratosis
1000–2700 r
10.2 Anogenital Warts/Condyloma

Author, year Total # of patients Method Results Comments
Moodley and 54 30 Gy in 10 30% complete Warts larger than 10 cm
Govender (2019) response in 83%, HIV+ in 96%
61% partial response
9% stable
Shah and Hertz 2 2015 rads over Transient responses Both of these giant
(1972) 3 weeks (250 kV) condylomas (GCA)
and 1736 rads over were included with 2
2 weeks (1 MV) other radiotherapy-
treated lesions in a 2001
review (Trombetta and
Place 2001)
74 D. Roberge
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natum of the anorectum: trends in epidemiology and
Diseases of Inflammation
David Roberge
Contents 1 Arachnoiditis
1 Arachnoiditis 77
Patients with symptomatic inflammation of their
2 Pancreatitis 78
2.1 Chronic Pancreatitis 78
meninges have been labeled with now defunct
2.2 Acute Pancreatitis 79 syndromes (for example, the optic chiasmatic
arachnoiditis named for professor Manuel Balado
3 Parotitis 79
3.1 Postoperative Parotitis 79 (Benaim 1949)) and treated on rare occasions
3.2 Other Etiologies of Parotitis 80 with empiric radiotherapy. I would assume that
4 Pyogenic Granuloma 80 many of these patients would today have a more
specific diagnosis, whether infectious, immune,
5 Sarcoidosis 81
5.1 Central Nervous System (CNS) 81
or oncologic. In this context, case reports of
5.2 Non-CNS Extrathoracic Involvement 82 radiotherapy would seem only of interest as his-
torical oddities.
6 Sinusitis 82
7 Tolosa-Hunt Syndrome 84
8 Tonsillitis 85
8.1 Historical Examples of Radiotherapy for
Tonsillitis 85
8.2 HIV-Related Tonsillar Hyperplasia 86
References 86
D. Roberge (*)
Department of Radiation Oncology,
Centre Hospitalier de l’Université de Montréal,
e-mail: david.roberge.chum@ssss.gouv.qc.ca

78 D. Roberge
Total #
of
Duke and 1 Surgical excision Transient clinical improvement All were cases of spinal
Hashimoto followed by radiotherapy after excision. Subsequent arachnoiditis occurring in
(1973) and corticosteroids for gradual deterioration. No the same family
subsequent deterioration response to radiation therapy or
corticosteroids
Feder and 17 600–800 r (air) in daily 4/17 excellent response with All of the patients had
Smith (1962) increments of 100–200 r return of both motor and chronic adhesive spinal
Area of cord involvement sensory function arachnoiditis and had been
is irradiated through 4/17 improved to a limited considered unsuitable for
posterior ports, 8 × 10 cm degree surgery
to 10 × 20 cm 5/17 arrest of the disease
If more than one port is 4/17 no response and no arrest
necessary, they are of progression
treated in rotation
Dickmann 7 No details provided 3/4 improved with immediate
et al. (1951) post-op radiotherapy
0/3 improved with late post-op
radiotherapy
Selinsky 5 800 r (in air) in All patients improved, 3 were
(1936) 100–150 r fractions re-treated
2 Pancreatitis and chronic alcohol abuse are implicated in the

etiology of approximately two-thirds of cases.
Acute pancreatitis is an inflammatory condition Acute pancreatitis can lead to chronic pancreati-
characterized by abdominal pain and elevated tis with its associated morbidity and repeated
levels of serum pancreatic enzymes. Gallstones hospitalizations.
2.1 Chronic Pancreatitis

Total # of
Guarner et al. 15 8 Gy single Response in 13/15 patients. 12 This was a prospective
(2009) fraction (2/15 were patients free of pain or repeat study
re-treated) flare-ups. Significant improvement in
QoL over baseline
Werner and 9 11–50 Gy over 6/9 patients completely relieved of 50 Gy was used in 1
Wetterfors 15–56 days (2/9 pain flares over ≥2 years patient because of an
(1973) were re-treated) erroneous diagnosis of
cancer
Volkova and 68 300–500 cGy in 54% complete pain response, 25% 12/16 patients had
Sharova 5–8 fractions partial response, 21% unchanged resolution of their
(1964) pancreatic fistula
Diseases of Inflammation 79
2.2 Acute Pancreatitis

Total # of
Wachtfeidl 96 50–150 cGy surface dose 9% mortality 64/96 postoperative
and Vitez daily (in 1–3 series pancreatitis
(1968) separated by days to
months) for a total of
100–1300 cGy
Rybakova 25 600–1800 cGy in air “Almost all patients after the 2nd to
(1957) (200 cGy fractions, 3rd session noted a significant
applied twice weekly) improvement,” “all patients left the
clinic in good condition”
Heacock and 53 200 cGy (in air) daily × 3 “Good” result in 62%
Cara Jr. (repeated 1–3 times in
(1954) 23%)
Levi and 28 75–150 cGy in air per 7% mortality 2/8 patients with
Engle (1950) fraction 1–3 times recurrent
pancreatitis were
re-treated
3 Parotitis Latchmore et al. 1940). With doubts on its effi-

cacy and certain long-term risks (notably in chil-
When not directly infectious in nature, inflamma- dren (Leake et al. 1971; Leake and Leake 1970)),
tion of the parotid can be dehydration related, radiotherapy is no longer part of the standard
autoimmune, iatrogenic, or of somewhat uncer- treatment of surgical parotitis.
tain etiology. Small case series and case reports are pub-
Once a common indication for radiotherapy, lished in Kimura’s disease (Ye et al. 2017), HIV-
postoperative suppurative parotitis has faded in related parotitis, as well as other rare situations
incidence as perioperative care has improved. At with parotid swelling. Although no indication
a time when it was more prevalent, radiation stands out as being well suited to radiation, a
treatment was of enough interest that the New variety of rare cases of parotitis may still be
England Journal of Medicine and The Lancet treated. In a German survey, 23 cases were irradi-
both featured articles on radiotherapy for postop- ated in the period of 1994–1996 (Seegenschmiedt
erative parotitis (Robinson and Spencer 1936; et al. 1999).
3.1 Postoperative Parotitis

Total # of
Keller et al. 43 100–1500 R (average 369 R)a 61%a “success” and 25%
(1968) without improvement or
deceased
Schumann and 99 Varied (78% < 200 cGy)a 67% cure, 27%
Keinert (1968) suppuration, 14% deatha
Krippaehne 40 Details unspecified 25% mortality (in keeping
et al. (1962) with mortality in group
treated without radiation)
Pendergrass 47 400–500 cGy in 3–4 fractions 68% “benefit”
and Hodes
(1942)
80 D. Roberge
Total # of
Fricke and 111 896–972 cGy surface dose 11.7% mortality Drainage less
Madding (radium blocks), repeated 1–2 commonly required in
(1942) times in a minority irradiated patients (8%
vs. 19%)
Robinson and 12 200–300 cGy orthovoltage 3/12 died despite
Spencer (1936) improvement of parotitis
a
Of a larger group of varied etiologies of parotitis
3.2 Other Etiologies of Parotitis

Total #
of
Author, year patients Indication Treatment Results Comments
Mourad et al. 30 HIV (benign 24 Gy in 12 93% response rate (80%
(2013) lymphoepithelial or 16 complete)
cysts)
Chitapanarux 6 Kimura’s disease 30–40 Gy 6/6 responded without any
et al. (2007) local recurrences
Chang et al. 3 Kimura’s disease 20–45 Gy in 2/3 recurred No correlation
(2006) 1.8–5 Gy between dose
fractions and local control
Hareyama 11 Kimura’s disease 20–44 Gy All patients responded but Authors
et al. (1998) 26% (of a larger group) recommend
recurred locally 26–30 Gy
Beitler et al. 12 HIV (benign 8–10 Gy in 100% response rate but
(1995) lymphoepithelial 2 Gy 92% relapsed at a median
cysts) fractions of 9.5 months
Itami et al. 10 Kimura’s disease 13–56 Gy All patients responded but
(1989) 21% (of a larger group of
lesions) recurred
Brady (1985) 1 Bulimia 7.2 Gy in 4 Initial response, recurrence
over the next 10 months for
which a second and
eventually 3rd course was
given
Glasenapp 5 Chronic recurrent 600 R/12 All free of recurrence
et al. (1970) parotitis over ≥1 year
2–4 weeks
Smith (1953) 2 Familial parotitis “Deep X-ray Durable response in both
therapy” cases
4 Pyogenic Granuloma Beyond cessation of an offending drug, a variety

of efficacious treatments are available—surgical,
Despite the implications of its name, pyogenic destructive (laser, cryotherapy, ligation), intrale-
granuloma is a noninfectious hyperplastic sional, or topical. Radiotherapy has only been
growth. It can be idiopathic or related to known administered in isolated cases.
stimuli, namely trauma or even antineoplastics.
Total # of
Author, year patients Site and age Treatment Results
Gunduz et al. 1 Conjunctiva, Following surgery for second No evidence of disease or
(1998) 53 years recurrence, 5 Gy over 1 h complication 1 year later
Aristizabal and 1 Middle ear, 2000 r/10 fractions, 23 days No evidence of disease,
Runyon (1981) 64 years normal hearing at >4 years
Hamilton et al. 2 Oral cavity, 600 cGy/3 Complete response without
(1968) 65 years 250 cGy/5 recurrence at 4–6 months
Lip, 40 years
Eisen (1940) 4 Thumb, 444–750 cGy in 4–5 weekly Complete response in all
54 years fractions cases
Finger,
36 years
Palm, 28 years
Finger,
27 years
ating granulomas is the hallmark of sarcoidosis,

5 Sarcoidosis it is mainly for involvement of other organs that
radiotherapy use has been reported—whether
Symptomatic sarcoidosis is predominantly man- brain, larynx, or penis. This limited literature
aged with corticosteroids. Several new options indicates responses by both physician report and
for systemic therapy are available for patients radiologic evaluation with the use of moderate
who are intolerant or resistant to steroids. doses of radiation in cases refractory of
Although involvement of the lung with noncase- steroids.
5.1 Central Nervous System (CNS)

Author, year Total # of patients Gender, age Treatment Results Comments
Sundaresan 1 F 38 years 24 Gy in 12 Complete response
and stereotactic
Jayamohan radiotherapy
(2008)
Motta et al. 1 F 41 years 26 Gy in 13, whole Complete remission
(2008) brain of most symptoms
Menninger 4 2F, 2M 15–25 Gy in 10–15 1 complete response, Responses
et al. (2003) 25–66 years fractions 2 partial responses were durable
(up to
204 months)
Kang and 3 3M, 23.4–24 Gy cranial 2/3 improved
Suh (1999) 21–46 years radiation, 21.6 Gy neurological
craniospinal symptoms
radiation
Stelzer et al. 1 M 22 years 20 Gy in 10 focal Complete response
(1995)
82 D. Roberge
Author, year Total # of patients Gender, age Treatment Results Comments

Ahmad et al. 1 F 26 years Cranial-spinal and Recovery of cranial Progressive
(1992) total nodal nerve palsies and CNS
irradiation, 20 Gy regression of involvement
adenopathy with
sustained excellent
outcome at 3-year
follow-up
Garcia- 1 M 24 years 30 Gy/3 weeks in 10 Partial response with
Monco and fractions to whole radiographic and
Berciano brain for meningitis clinical improvement
(1988) for 1 month
Gelwan et al. 4 (visual 1F, Low doses of 10 Gy Only transient benefits
(1988) deterioration 3M/20– repeated to total
with disease in 45 years doses of 48.4 Gy to
anterior visual pituitary/sellar area
pathways) and/or anterior
cranial fossa
Bejar et al. 1 M 44 years 30 Gy in 3 Gy Complete resolution 1-year
(1985) fractions of radiographic follow-up
findings with signs
and symptoms
Grizzanti 1 M 26 years Whole-brain Responded
et al. (1982) radiation, 10 Gy in dramatically. Died
2 Gy fractions 1 year later of other
causes. Had fibrotic
granuloma in brain
5.2 Non-CNS Extrathoracic Involvement

Total # of Gender,
Author, year patients age Treatment Results Comments
Tanaka 1 (Bone) M 20 Gy Complete clinical Cord compression
et al. (2018) 68 years response and significant treated prior to the
radiological response diagnosis of
sarcoidosis
Frizzell 1 (Skin) F 30 Gy in 12 Complete response at
et al. (2002) 35 years 24 months
Fogel et al. 1 M 30 Gy in 3 Gy Complete resolution
(1984) (Larynx) 36 years fractions 16 months after treatment.
Confirmed by tomograms
Whittaker 1 (Penis) M Partial amputation Dramatic improvement 1-year follow-up
et al. (1975) 59 years and steroids with
recurrence in
1 month
6 Sinusitis have been reported (Calabrese and Dhawan

2013). Although responses were common in
Prior to the arrival of antibiotics in the 1940s, most scenarios (notably less in atrophic sinus-
radiotherapy had been used for a wide range of itis), these treatments are now simply of histori-
sinus conditions. Approximately 3000 such cases cal interest.
Total # of
Levy (1951) 109 50 r per field (3 fields) 60% “good” results Antibiotic-refractory
weekly for 5–10 weeks 22% “fair” results subacute or chronic
18% “poor” results sinusitis
Laing (1948) 900 240 r in 3 fractions over 71% “cured” after Subacute sinusitis
8 days one course
15% “moderate
improvement”
14% “temporary”
improvement or no
response
Haines (1943) 105 Four weekly fractions of 98% “pleasing
(10–60 years 150 r (air) results”
of age)
Crang (1943) 57 100 R (in air) twice a week 46% “excellent” Cases of acute, subacute,
for 4–5 treatments results and chronic sinusitis
14% “fair” results
40% “poor” results
Youngs (1941) 75 400–1480 r (air) in 1–4 21% “cured” Chronic sinusitis
fractions 41% “markedly
improved”
37% no benefit
Pendergrass 122 (98 Typically 50 r (skin dose) Adults Acute and chronic
and Hodes adults, 24 per each of 4 fields, 1 field 24% complete sinusitis
(1941) children) per day for a total of 6 days response
19% “moderate”
relief
57% little or no relief
Children
84% complete
response
8% “moderate” relief
8% little or no relief
Gatewood 22 Not specified 4 complete response Chronic sinusitis
(1940) 8 partial response
10 no improvement
Maxfield Jr 57 Varied, typically single 18% “cured” Mix of acute and chronic
and Martin fraction ≥400 r 32% improved cases. None cured of
(1940) 47% unchanged chronic complicated
sinusitis
Butler and 450 300 r (in air) repeated at 36% symptom-free Chronic sinusitis
Woolley 6–8 weeks if partial 55% improved
(1942) response
Rathbone 120 children 100–120 r (in air) per field, 57% cured Chronic sinusitis
(1937) (70 with one field per day, 3 28% improved
follow-up) treatments per week over 15% not improved
2 weeks
Williams and 88 80–150 r (acute cases 66–75% (Had also treated 53
Bryan (1936) treated daily (average 3.4 symptom-free cases of bronchitis and
fractions), chronic cases on 11–12.5% improved 170 cases of rhinitis)
alternate days (average 4.5 11–12.5% no change
fractions))
84 D. Roberge
Total # of
Warren (1935) 72 Single dose 900 r 25 “marked” Includes cases of allergic,
improvement infectious, and polypoid
40 “moderate” sinusitis
improvement
20 transient
improvement
15 no improvement
Osmond 12 1–7 fractions of X-ray All patients Acute sinusitis. First
(1923) therapy symptomatically treatment given in 1916
relieved (motivated by relief seen
after diagnostic X-rays)
• Granulomatous inflammation of the cavern-

7 Tolosa-Hunt Syndrome ous sinus, superior orbital fissure, or orbit,
demonstrated by imaging or biopsy
Tolosa-Hunt syndrome is described as an epi-
sodic orbital pain associated with paralysis of As the syndrome is rare and without a specific
one or more of the third, fourth, and sixth cranial diagnostic test, the findings must not be better
nerves, which resolves spontaneously but may accounted for by another diagnosis. The treat-
relapse and remit. Since the original description ment of choice is steroids. Occasionally, other
in 1954 (Tolosa 1954), diagnostic criteria have immunosuppressive therapies have been used
evolved to include (Headache Classification when patients are refractory or intolerant to
Committee of the International Headache Society steroids.
(IHS) 2018): There are a limited number of case reports of
response followed by durable remission with
• Unilateral headache ipsilateral to the other focal radiation.
findings which has preceded paresis of one or
more cranial nerves
Total # of
Lee et al. 1 14 Gy Complete response of pain and
(2016) radiosurgery oculomotor palsy. Steroids tapered and
patient free of recurrence beyond
2 years
Furukawa 1 30 Gy in 15 Durable response for >1 year Patient had
et al. (2010) 3DCRT contraindication to
corticosteroids
Foubert- 1 20 Gy in 10 Durable response without steroids
Samier et al. (>8 years)
(2005)
Mormont 1 30 Gy in 15 Clinical and MRI response for >3 years
et al. (2000) post-cessation of immune suppression
Larner et al. 1 20 Gy in 10 Complete response of ophthalmoplegia
(1991) allowing for cessation of steroids
Nasr et al. 1 50 Gy through Significant clinical response maintained
(1987) lateral opposed despite complete steroid withdrawal
fields
Luchin et al. 1 60 Gy in 3 Complete clinical and radiological
(1987) (proton therapy) recovery durable for >4 years
8 Tonsillitis tumors, and neural tumors (Christensson 1978;

Hazen et al. 1966; Ju 1968; Modan et al. 1974;
Radiation can reduce acutely or chronically Rao 1980; Schneider et al. 1978; Shore-Freedman
inflamed tonsils. Although radiotherapy was et al. 1983; Van Den Berg and Edis 1980) These
never broadly favored over surgery, it was vari- risks are more pronounced in young patients. In
ably used to induce tonsillar atrophy—notably in the follow-up of 2311 patients who received irra-
patients “mentally,” “physically,” or “commer- diation for inflamed tonsils and adenoids during
cially unfit” for surgery (Corbett 1924). Radiation childhood, there were 31 neural tumors and 54
was delivered through intraoral application of salivary gland tumors (Shore-Freedman et al.
radium (more rarely externally applied) of exter- 1983). Although in 1975 Russian physicians
nal kilovoltage X-rays (more rarely intraoral reported 32P plaque applications for tonsillitis
superficial X-rays). Although these treatments (Filatov et al. 1975), a 1976 survey of 49 aca-
may provide benefit, there are clear long-term demic and private practice centers revealed con-
sequelae to radiation treatment that include thy- sensus for nontreatment of tonsillitis with
roid tumors, salivary gland tumors, parathyroid irradiation (Kopicky and Order 1977).
8.1 Historical Examples of Radiotherapy for Tonsillitis

Total # of
Filatov et al. 62 (18 acute, Custom 32P Positive effects in
(1975) 44 chronic) applicator terms of clinical
25 Fer (22.25 cGy) improvement (acute)
per fraction, 50 Fer and absence of
total in acute, and recurrence (chronic)
75–100 in chronic
tonsillitis
Derr (1953) 1500 160 R per field, first 493/572 “obtained “My own family of five have all
treatments 1 week good results” had X-ray treatment of the
apart, then every tonsils. Two of us, my wife and
2 weeks for a total I, had trouble years after
of 5 tonsillectomy. The treatment
entirely cleared up the trouble”
Uhlmann 480 375 r in 3 fractions 25% complete
et al. (1948), resolution of
Uhlmann symptoms
(1956) 45% “considerable
improvement”
17% temporary
improvement
12% no improvement
<2% worsening
Calvet 72 Intraoral X-rays 4–6 “Healing” in 50%
(1947) fractions of 500 r Marginal results in
(air) weekly or 30%
every other week Poor results in 20%
Scal (1927) 18 (a) Radium needles Tonsillar atrophy in all The one patient not improved
(b) Permanent glass patients and improved was treated with hopes of
radon seeds symptoms in most improving Graves’ orbitopathy
(c) Removable
platinum radon
seeds
86 D. Roberge
Total # of
Williams 101 (44 50 mg radium 41/44 reduced in size
(1922) enlarged bromide for 31/33 reduced (2 lost
tonsils, 33 10–20 min per to follow-up)
tonsillitis (2 tonsil 11/14 arthritis
acute), 14 diminished or
arthritis) disappeared
Robinson 75 Radium (a) More or less
(1922) (a) 50 mg tube complete atrophy
applied externally 25/30
for 6–10 h (b) 25/25 responded
(b) Two 12.5 mg (c) Results “similar” to
needles inserted for b (20 patients)
2–4 h
(c) 20–30 mg
plaque held against
tonsil for 1–2 h
8.2 HIV-Related Tonsillar Hyperplasia

Author, year Total # of patients Treatment Results Comments
Goldman et al. (2014) 1 30.6 Gy in 17 Asymptomatic 3 years
fractions posttreatment
Grobbelaar et al. 13 24 Gy in 12 fractions Tonsil size decreased in all patients
(2008)
Epstein et al. (1995) 1 Unspecified Successful shrinkage
Butler FE, Woolley IM (1942) The present status of roent-

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(1999) Strahlentherapie von gutartigen Erkrankungen:
Endocrinological Disorders
Tyler Safran and Daniel Juneau
Contents 1 Gynecomastia
1 Gynecomastia 89
1.1 Prevention of Gynecomastia 90 Gynecomastia is the benign proliferation of glan-
1.2 Treatment of Gynecomastia 92 dular tissue affecting more than half of men to
1.3 Prevention and Treatment 93 some degree throughout their lives (Niewoehner
2 Hyperthyroidism 94 and Nuttal 1984). The etiology is multifactorial;
2.1 Selected Studies on the Efficacy of I131 however, it involves a decrease in systemic andro-
Therapy for Hyperthyroidism 95
2.2 Long-Term Follow-Up Studies in Patients
gens, increase in estrogen, or an enhanced tissue
Treated with I131 for Hyperthyroidism 101 estrogen sensitivity (Georgiadis et al. 1994).
Hormonal imbalances may be secondary to sys-
References 101
temic illnesses, hypogonadism, diet, lifestyle
choices, or certain medications; in all circum-
stances, treatment begins with conservative
approaches aimed at addressing the underlying
pathology with lifestyle modifications, consulta-
tion with an endocrinologist, and assessment of
current medications (Di Lorenzo et al. 2005).
Patients with recalcitrant disease may offer a
variety of invasive approaches; more localized
cases are amenable to liposuction, while for true
symptomatic gynecomastia, surgery is accepted
as a standard of care (Fruhstorfer and Malata
2003). While severe cases may require full mas-
tectomies with free nipple grafts, this option is
often reserved for the highest grades given scar
burden and risk of nipple loss (Johnson and
Murad 2009). In patients who are not surgical
candidates, or who are placed on DES or femi-
nizing hormones, radiation therapy can play a
T. Safran (*) · D. Juneau role in prevention or treatment. With the chang-
Division of Plastic Surgery, McGill University Health
ing landscape of hormonal therapy for prostate
Center, Montreal, QC, Canada
e-mail: Tyler.safran@gmail.com; cancer, radiotherapy is now less commonly used
tyler.safran@mail.mcgill.ca in these indications.

Published Online: 18 March 2023
90 T. Safran and D. Juneau
1.1 Prevention of Gynecomastia
Average Side effects/

Authors Patient information Intervention details follow-up Outcomes complications
Ozen et al. 125 patients with 1200 rad electron 1 year Gynecomastia None
(2010) localized prostate beam in 2 incidence in the control
cancer randomized fractions on group vs. intervention
1:1 to XRT prior to consecutive days group was 31.9% and
bicalutamide or 12% at 3 months,
bicalutamide alone 40.3% and 19.6% at 6,
and 50.8% and 15.9%
at 12 months,
respectively (p < 0.001)
Tyrrell 106 patients with Single 1000 rad 1 year Gynecomastia Complications
et al. localized prostate dose of electron incidence in the control experienced by
(2004) cancer randomized beam group vs. intervention 17/52 patients
1:1 to XRT prior to radiotherapy group was 85% vs. (breast/nipple
bicalutamide or 52%, respectively erythema,
sham radiotherapy (p < 0.001) breast/nipple
prior to Severity of tenderness, and/
bicalutamide gynecomastia lower in or skin
radiation group irritation)
(p < 0.001), and of
slower onset
Mammalgia incidence:
in the control group vs.
intervention group was
91% vs. 83%
Widmark At the discretion Radiation was 1 year Gynecomastia Radiotherapy-
et al. of the physician delivered incidence in the control induced
(2003) and patient, immediately group vs. intervention mammalgia and
174/253 patients before group was 71% vs. skin reactions
with locally gynecomastia- 28%, respectively at 3 months
advanced prostate inducing therapy (p < 0.001) postirradiation;
cancer treated total as either electron Breast tenderness incidence not
androgen block beams or incidence in the control specified
(TAB) received roentgen. Doses vs. intervention group
prophylactic breast ranged from was 75% vs. 43%,
radiotherapy 1200 to 1500 rad respectively
in 1–3 fractions Breast tenderness
significantly higher at
3 months in
radiotherapy group due
to skin reactions
Fass et al. N = 87 patients XRT either 4 years Gynecomastia Allergic
(1986) had prostatic before or shortly incidence: n = 20/87 reaction to
carcinoma and had after starting (mild n = 9, moderate marking dye:
started, or were to gynecomastia- n = 11, severe n = 1) n = 2/87
begin, a course of inducing therapy Mammalgia incidence:
diethylstilbestrol 5/87 received less n = 15/87 (mild n = 11,
than 1200 rad, moderate n = 4)
43/87 patients
treated with
1200 rad, 39/87
received 1500 rad
as a single
fraction
Endocrinological Disorders 91
(continued)
Waterfall Randomized trial 27 patients were 18 months Gynecomastia Erythema:
and Glaser of 47 patients with randomized to incidence in the control n = 1/27
(1979) a histological 900 rad to the group vs. intervention
diagnosis of breasts given as group was 85% vs.
prostatic three 300 rad 11%, respectively
carcinoma, treated treatment on 3 (statistical analysis not
with either 100 mg consecutive days provided)
tetrasodium
testestrol three
times daily or
stilboestrol 5 mg
three times daily
for 2 weeks;
maintenance
therapy thereafter
as stilboestrol
3 mg per day
Brown and N = 13 patients XRT 17 months Gynecomastia Brown
Rubenfeld with prostatic immediately (6–48 months) incidence: n = 3/13 pigmentation of
(1974) carcinoma treated before starting (minimal n = 3). the nipple and
with 1 mg of gynecomastia- Tenderness incidence: areola: n = 1/13
stilbestrol per day; inducing therapy. n = 6/13 (minimal Allergic
all had bilateral 5/13 patients n = 5; moderate n = 1). reaction to the
orchiectomies received a dosage Mammalgia incidence: marking pencil:
of 1500 rad to n = 0/13 n = 1/13
each breast,
delivered in 5
fractions over an
elapsed time of
7 days. In the
remaining
patients, doses
varied from 800
to 1200 rad in
shorter or longer
times, up to 8
days
Cook and N = 50 patients Surface dose of 11.2 months Gynecomastia Skin changes
Rodriguez- with a diagnosis of 900 rad to each (1–36 months) incidence: n = 17/50 and pain:
Antunez prostatic breast in a single (minimum n = 5, n = 1/50
(1973) carcinoma on fraction moderate n = 11, severe
Case Series estrogen therapy n = 1)
Overall mammalgia
and/or nipple pain or
tenderness incidence:
n = 33/50 (minimum
n = 4, moderate n = 18,
severe n = 1)
Corvalan N = 20 patients Surface dose of 15.5 months Gynecomastia Erythema and/
et al. with metastatic 900 rad to each (4–33 months) incidence: n = 3/20 or skin
(1969) prostatic breast in a single (minimal n = 3) discomfort:
adenocarcinoma fraction Mammalgia incidence: n = 6/20
treated with n = 3/20 (minimal
diethylstilbestrol n = 3)
(continued)
(continued)
Alfthan N = 78 patients 2 weeks before 58% ≥1 year Gynecomastia Mild erythema
and Holsti with prostatic staring developed in 70/78 occurred in
(1969) carcinoma. gynecomastia- (90%) of patients’ some cases
Polyestradiol inducing therapy, unirradiated breasts; after a single
phosphate given left breasts were “pronounced dose of 1000 or
intramuscularly treated (right gynecomastia 1250 rad, but
(80 mg once a breasts were inhibition” in the no major
month); 8 patients untreated) irradiated breast in 65 discomfort was
received a course 58/78 received a of these 70 patients experienced.
of single treatment 26/65 patients had Incidence not
chlortrianidestrol with a skin dose reduced or absent disk specified
6 mg of 800, 1000, or formation, 25/65
TID. Orchiectomy 1250 rad. 20/78 reduction of disk
in 47 patients given formation and reduced
two doses of fatty deposits, 14/65
800 rad with an demonstrated reduction
interval of of fatty deposits only
1 week
Larsson N = 6 patients with XRT 14 days 6–9 months Gynecomastia Temporary
and prostatic before starting developed in 4/6 (67%) erythema and
Sundbom carcinoma gynecomastia- of patients; no pigmentation
(1962) receiving inducing therapy significant reported but
chlorotrianisene Single roentgen gynecomastia observed incidence not
48 mg daily orally, treatment with a in irradiated breasts of specified
for 6–9 months skin dose of these patients
1000–1500 rad (incidence 0%)
Histologic examination
showed significantly
reduced gland size and
number of ducts.
Degree of activity of
duct epithelium
unchanged
1.2 Treatment of Gynecomastia
Intervention Average Side effects/

Authors Patient information details follow-up Outcomes complications
Van N = 41 patients Two 6 Gy 6 months In a population of 51 Breast/nipple
Poppel with nonmetastatic fractions on patients on erythema
et al. adenocarcinoma of consecutive days bicalutamide, incidence n = 15/41
(2005) the prostate using electrons of gynecomastia was Skin irritation
receiving 72.5%; incidence of n = 13/41
bicalutamide breast pain was 80.4% Lethargy n = 1/41
150 mg once daily Of the 41 patients
receiving radiation
therapy as treatment for
early gynecomastia and/
or breast pain,
resolution was achieved
in 7.3%, improvement
in 29%, no change in
22%, and symptom
progression/worsening
in 24.4%
(continued)
Chou 11 patients with XRT 1–22 months 27.3 months 11/11 patients had Acute
et al. metastatic prostate after starting (1–60 months) satisfactory pain relief complications
(1988) cancer treated with gynecomastia- at the final follow-up, consisted of
orchiectomy and inducing therapy while 8/11 had complete various degrees
diethylstilbestrol (average pain relief. The time of erythema and
1–4 mg per day 9.4 months) for intervals between dryness. No late
the palliative conclusion of complications
management of radiotherapy to were noted
mammalgia complete relief varied
Doses varied from from 2 weeks to
20 Gy in 5 14 months (average
fractions to 40 Gy 3.6 months). More pain
in 20 fractions. relief was observed in
3/11 patients were patients with initially
treated with more severe
electron beams; mammalgia. 3/11
8/11 with patients also noted
100–150 kVp significant decrease in
X-rays breast size
1.3 Prevention and Treatment

Perdona 151 patients with prostate Single 25 months Prophylaxis— Rash and/or
et al. (2005) cancer randomized 1:1:1 to 1200 rad (12– Gynecomastia nipple
bicalutamide, radiotherapy 35 months) Incidence: erythema:
bicalutamide + XRT, or dose Bicalutamide alone n = 19/50
bicalutamide + tamoxifen 69% Skin irritation:
10 mg for 24 weeks XRT before n = 19/50
35 patients originally bicalutamide treatment Pruritis:
randomized 1:1 to 34% (p = 0.008) n = 2/50
bicalutamide were Bicalutamide
subsequently randomized to treatment with 10 mg
XRT or tamoxifen when tamoxifen 8%
they developed (p = 0.0009)
gynecomastia or breast pain Prophylaxis—
Mammalgia Incidence:
Bicalutamide alone
57%
XRT before
bicalutamide treatment
30% (p = 0.002)
Bicalutamide
treatment with 10 mg
tamoxifen 6%
(p = 0.009)
Gynecomastia
Treatment:
XRT resolved 8/18
cases, while tamoxifen
resolved 15/17
(continued)
(continued)
Srinivasan N = 42 patients with Radiation 19 months Gynecomastia and/or Mild
et al. (1972) prostatic carcinoma. 35 dose of mammalgia incidence: mammalgia
patients received 5 mg of 1200 rad to XRT (intervention) n = 2/39
stilbestrol daily, 6 patients each breast group 5%; Erythema
received >5 mg of (maximum Mastectomy n = 1/39
stilbestrol daily, and 1 dose (comparator) group Pruritis
patient was on 1460 rad) 16% n = 1/39
chlorotrianisene 12.5 mg given over In patients treated with
daily 11 fractions XRT for estrogen-
39/42 patients managed induced gynecomastia,
prophylactically; 3/42 full resolution of pain
patients treated with XRT and tenderness in all 3
after gynecomastia onset patients, but
persistence of
gynecomastia
2 Hyperthyroidism safety of RAI, with a focus on its potential carci-

nogenic effect. There are contraindications to
Radioactive iodine (RAI) is an effective and treatment with radioiodine, mainly pregnancy
common treatment for hyperthyroidism caused and breastfeeding (Ross et al. 2016). Pregnancy
by Graves’ disease, toxic adenoma, and multi- is an absolute contraindication to RAI treatment,
nodular goiter. For decades prior to the discov- since iodine can cross the placenta and be taken
ery of I131 in 1938, radium and X-rays were used up by fetal thyroid tissue. Lactation is associated
in the treatment of hyperthyroidism (Kempster with an increase in breast sodium iodide sym-
1933). This led to slow responses and debates porter activity. As such, breastfeeding needs to
with surgeons (Joll 1933). It is only in 1941 that be discontinued before RAI. Most sources rec-
radioiodine produced at the Massachusetts ommend breastfeeding be discontinued for at
Institute of Technology was first used in the least 6 weeks prior to RAI. The American
treatment of hyperthyroidism (Hertz et al. 1942). Thyroid Association (ATA) recommends pre-
It is now considered a first-line treatment due to treatment with methimazole in a variety of clini-
its low cost and safety. Table 1 summarizes cal situations, and as such consultation in
selected studies on the efficacy of RAI therapy endocrinology is essential prior to radioiodine
for hyperthyroidism and provides an overview of treatment (Ross et al. 2016). Radioiodine is
the history of treatment and how it has changed given orally as sodium iodide (I131) and, once in
throughout the years. One recent meta-analysis the thyroid, releases beta emissions that directly
demonstrated that when compared to antithyroid damage the tissue (Abraham and Acharya 2010).
drugs, radioiodine was associated with a higher These electrons have a maximum energy of
cure rate and a lower rate of relapse. While the 0.61 MeV, an average energy of 0.192 MeV, and
treatment is generally considered safe and is a range in tissue of 0.8 mm. I131 has a half-life of
associated with a lower overall rate of adverse just over 8 days. In most jurisdictions, treatment
events when compared to antithyroid drugs, it is can be performed on an outpatient basis.
also associated with an increased risk of new or Depending on the dosage, the patient may need
worsening ophthalmopathy and a higher rate of to follow radioprotection rules to avoid exposing
hypothyroidism (Wang and Qin 2016). Table 2 the public and other household members to
includes a few selected studies on the long-term unnecessary radiation.
Following treatment, patients are monitored and exacerbation of orbitopathy. A minority of

for hypothyroidism. Using modern protocols, patients (up to 20%) will fail to achieve a per-
cure rates of more than 80% are usually sistent response following their first treatment
achieved following a single treatment, and a and will go on to require a second treatment.
significant proportion of patients will eventu- Women of childbearing age should be advised
ally develop hypothyroidism (Table 1). The to avoid pregnancy for at least 6 months follow-
most commonly observed side effects of RAI ing RAI, while men should be advised to avoid
include thyroiditis, rebound hyperthyroidism, conception for 3 months.
2.1 Selected Studies

on the Efficacy of I131 Therapy
for Hyperthyroidism

Metso et al. 2043 Fixed 7 mCi The remission rate did not
(2004) (259 MBq) dose of differ between the patients
RAI who received a dose of
RAI calculated according
to the uptake of RAI and
thyroid size and those
who received an empirical
dose of RAI. The fixed
7 mCi (259 MBq) dose of
RAI cured 80% of
patients
Allahabadia 813 443 patients were Patients given a single Male patients and those
et al. (2000) 321 Graves’ treated with a first dose of 370 MBq had a with more severe
disease dose of 185 MBq, and higher cure rate than those hyperthyroidism and
126 toxic 370 received a given 185 MBq (84.6% medium- or large-sized
nodular 370 MBq dose vs. 66.6%, P < 0.0001), goiters are less likely to
hyperthyroidism but an increase in respond to a single dose
366 hypothyroidism incidence of radioiodine; the
indeterminate at 1 year (60.8% vs. authors suggest that the
etiology 41.3%, P < 0.0001) value of higher fixed
initial doses of
radioiodine should be
evaluated in these
patient categories with
lower cure rates
Leslie et al. 88 Low-fixed, 235 MBq; Mean treatment doses The use of a fixed dose
(2003) high-fixed, 350 MBq; were similar in the method simplifies the
low-adjusted, different outcome groups. approach to treatment
2.96 MBq (80 Ci)/g The authors could not with potential cost
thyroid adjusted for demonstrate any savings
24 h radioiodine advantage to using an
uptake; and high- adjusted dose method.
adjusted, 4.44 MBq Survival analysis did not
(120 mCi)/g thyroid demonstrate any
adjusted for 24-h difference in the time to
radioiodine uptake outcome between the
fixed and adjusted dose
methods
(continued)
(continued)
Thjodleifsson 174 1. I131: Average initial 1. 29/37 (78.3%) Graves’ disease
(1975) dose 4.8 mCi (37 pts) euthyroid
2. Thyroidectomy 7/37 (18.9%) hypothyroid
(137) 2. 93/137 (67.9%)
euthyroid
11/137 (8.1%)
hypothyroid
33/137 (24%) relapses
Cevallos et al. 102 I131 Low dose: Graves’ disease
(1974) Low dose: Mean 56/102 euthyroid
thyroid dose of 19/102 hypothyroid
5578 rad 27/102 hyperthyroid
High dose: mean High dose:
thyroid dose of 17/35 euthyroid
9986 rad 16/35 hypothyroid
Tunbridge 105 I131: details not given 2-year follow-up: Author measured TSH
et al. (1974) 85/105 (81%) euthyroid levels, serum
13/105 (12%) triiodothyronine levels,
hypothyroid serum protein-bound
iodine, and serum
thyroxine
Blahd and 241 I131 Percentage hypothyroid All had Graves’ disease.
Hays (1972) Dose calculated to (corrected for the length The entire patient
give 5900–6000 rad to of follow-up): population in this series
the thyroid. Estimated 10.4% at 1 year was male. Percentage
thyroid gland weight 21.2% at 5 years hypothyroidism
was obtained by 39.5% at 10 years increased by an
empirical weight 70.8% at 15 years increment of 2.7% per
calculations. 132 year in years 1–5, 3.7%
patients received 1 per year in years 5–10,
dose, 72 patients and 63% per year in
received 2 doses, 36 years 10–15
patients received 3 or
more doses
McDougall 74 Combined Standard dose group:
and Greig carbimazole—I131 16/38 (42.1%) euthyroid,
(1972) treatment: 14/38 (36.8%) relapsed,
Carbimazole given for 8/38 (21.1%) hypothyroid
5 months stopped for Low dose: 16/36 (44.4%)
2 weeks when the euthyroid, 17/36 (47.2%)
dose of I131 was given, relapsed, 3/36 (8.4%)
was restarted 1 week hypothyroid
later, and was
continued for 5 more
months (1 mg
thyroxine daily was
also given during this
last phase)
2 dose regimes:
Standard dose (mean
dose of 7.6 mCi), low
dose (mean dose of
3.8 mCi). The two
doses differ by a
factor of 2
(continued)
Sachs et al. 603 I131: Using life table method.
(1972) Dose, majority 12.3% hypothyroidism at
received 3–6 mCi the end of 1 year
2.5% became hypothyroid
in the second year
Decreasing incidence of
hypothyroidism was
found at 11 years, 40%
hypothyroid, overall
incidence of 23.6%
Jackson 131 The majority of 1-year follow-up: 20% required two or
(1971) patients received 85/93 (91.3%) euthyroid, more treatments
1–4 mCi total dose of 5/93 (5.3%) hypothyroid,
I131 2-year follow-up: 62/66
(93.9%) euthyroid, 4/66
(6%) hypothyroid. Total
series results (minimum
of 3-month follow-up):
112/131 (85%) euthyroid,
15/131 (11%)
hypothyroid
Lewitus et al. 99 1. Small dose I125 1. 18/45 fair-good results,
(1971) (average 2.5 mCi) (45 3/45 permanent
patients) hypothyroidism
2. Intermediate dose 2. 6/11 good results, 1/11
I125 (11 patients) hypothyroidism
3. I125 (average dose 3. 39/43 fair-good results,
3 mCi) plus I131 3/43 hypothyroidism
(average dose
3.8 mCi) (43 patients)
Franco et al. 18 I131 5 mCi and Follow-up of 2–16 months. Diagnosis:
(1970) propranolol 10–40 mg Symptomatic improvement In all patients, diffuse
q.i.d. (Propranolol was was immediate. No thyroid hyperplasia with
discontinued when laboratory or clinical hyperthyroidism
there was no relapses. 5/18 developed
additional clinical clinical and/or laboratory
need for symptomatic signs of hypothyroidism
treatment) and were put on
replacement therapy
Viherkoski 387 Pretreatment with Incidence of
et al. (1970) carbimazole in 55 hypothyroidism at 1 year:
(14%) 11.8% toxic nodular
I131 dose calculated to goiter, 25.6% toxic diffuse
give 100–130 μCi/g in goiter. Yearly increment
diffuse goiter and of 10.2%. 14% of the
140–160 μCi/g in patients were pretreated
nodular goiter with antithyroid drugs. In
Posttreatment with those not so treated,
carbimazole in 186 severe posttreatment
(43%) reactions occurred in 4%.
In addition, the incidence
of hypothyroidism was
lower in the group of
patients treated without
carbimazole or with only
posttreatment carbimazole
(21–22%)
(continued)
(continued)
Kaipainen 243 I131: At 1 year:
et al. (1970) 5.5 mCi 22% hyperthyroid
7.4% hypothyroid
At 2 years:
11% hyperthyroid
8.6% hypothyroid
Burke (1969) 484 I131: Incidence of Graves’ disease
Mean therapeutic dose hypothyroidism:
was 8.9 + 7.2 mCi 31% at 1 year
44% at 5 years
54% at 8 years
Goolden and 181 I131 therapy: Follow-up of 1 year Pretreatment with
Fraser (1969) Dose, 150 μCi/g of Carbimazole plus I131: carbimazole did not
thyroid tissue. 83 63% euthyroid significantly alter
patients were given 14% hypothyroid subsequent response to
pretreatment with 23% toxic I131 therapy
carbimazole for I131 only:
2–4 months 57% euthyroid
13% hypothyroid
20% toxic
Reinwein 310 I131 therapy: 294/310 (95%) euthyroid, Follow-up of
et al. (1969) Fractionated therapy. 7/310 (2%) hypothyroid, 2–11 years, 4 of the 7
Mean total dose of 9/310 (3%) hyperthyroid cases of hypothyroidism
5.4 mCi in patients had subtotal
without a goiter and thyroidectomy in
7.1–12.9 mCi in addition to radioiodine
patients with a goiter. therapy. Subtotal
Mean number of doses thyroidectomy in
was 1.7–2.7 addition to radioiodine
therapy was done in 27
cases. Some patients
also received
premedication or interim
treatment with
antithyroid drugs
Feibush and 149 I131 therapy: 12/149 (8.6%) Minimum follow-up of
Sherman Dose, 2–4 mCi (first permanently hypothyroid 3 years; 9 of 12 patients
(1968) dose) up to a who became
maximum of 15.2 mCi permanently
(total dose) hypothyroid did so
56.4% received only 1 within 6 months
dose following therapy
Hamburger 356 I131: Large dose (56):
and Paul Large dose: initial or 36/56 euthyroid, 19/56
(1968) subsequent dose of hypothyroid.
20 mCi or greater Conventional dose (302)
82% euthyroid after a
single dose. The
remaining 18% required
two or more doses
(continued)
Hagen et al. 116 Low dose: 80 μCi 90/116 (77%) euthyroid 36 patients were
(1967) I131/g thyroid tissue after one dose pretreated with
followed by potassium 7/116 (6%) permanently thiouracil derivative, but
iodide therapy in 97 hypothyroid there were no
patients complications in this
group as compared to
those without treatment.
Mean follow-up period
of 1.9 months
40 High dose: 160 μCi 16/40 (40%) euthyroid Mean follow-up period
I131/g thyroid tissue after one dose of 11 months
13/40 (33%) permanently All patients in both
hyperthyroid goiters groups had diffuse
goiters
Smith and 539 1. Conventional dose At 1 year:
Wilson (271 patients) 1. 47.9% euthyroid
(1967) 5.0 + 2.0 mCi 44.2% hyperthyroid
2. Half dose (268 7.9% hypothyroid
patients) 2. 30.8% euthyroid
2.8 + 1.6 mCi 65% hyperthyroid
4.3% hypothyroid
Tezcan et al. 120 I131 therapy: Follow-up of 12 years Multinodular (17)
(1967) Dose, 3–5 mCi initial Overall results: Diffuse (98)
dose (total dose 100/120 (83%) euthyroid Toxic nodule (5)
ranged from 3 to 16/120 (13.3%) The incidence of
greater than 20 mCi, hypothyroid hypothyroidism was
but the majority of 4/120 hyperthyroid highest in the
patients received less Based on group at risk multinodular group
than 10 mCi total follow-up: (12.5%). It was only
dose) 11/120 (9.2%) 6.7% in the diffuse
hypothyroid at 1 year group, and 0% in the
9/33 (27.3%) hypothyroid toxic nodular group
at 5 years 4/120 had prior drug or
surgical treatment
Donovan and 170 I131 therapy: Follow-up of 11 years: 21/22 who developed
Turtle (1966) Dose: 5–12 mCi initial 22/170 (13%) hypothyroidism did so
dose ranged from 5 to hypothyroid, 11/170 within the first 2 years
79 mCi. 111 (65%) (6.5%) were not following treatment
were controlled with a controlled by I131 and
single dose; 48 (28%) required other forms of
required multiple treatment or additional I131
doses
Edsmyr and 2035 I131: First 796 cases, minimum No palpable goiter
Einhorn Dose, calculated to follow-up after 2 years (541). Diffuse
(1966) give 5000–12,000 rad 7.5% Hypothyroidism enlargement of the
within 1 year. Annual thyroid gland (811)
increment of 3–27% Nodular goiter (683)
hypothyroid at 7 years 9 deaths within 1 month
of therapy, 3 of these
possibly due to an
exacerbation after
treatment
(continued)
(continued)
Nofal (1966) 969 I131 (848 patients) I131 treated: Thyroid size at treatment:
average dose of 44% hypothyroid at 1 year. I131:
10 mc. 2/3rd of the Cumulative percentage of 13% normal
patients received hypothyroidism increased 6.7% not palpable
antithyroid 5.5%/month during the first 53.9% diffusely enlarged
medications prior to 6 months, 1.3%/month 9.1% enlarged, solitary
I131 therapy or surgical during the second 6-month nodules
treatment (121 period and 2.8%/year 17.1% enlarged, multiple
patients) thereafter nodules
Surgically treated: Surgery:
27% hypothyroid at 1 year. 2.5% normal
Cumulative percentage of 0% not palpable
hypothyroidism increased 68.6% diffusely enlarged
3.7%/month during the first 14.9% enlarged, solitary
6 months, 0.51%/month nodules
during the second 6-month 14% enlarged, multiple
period, and 1.7%/year nodules
thereafter
Säterborg and 157 I131 therapy: 1. Nonfractionated All of the patients had
Einhorn 1. Nonfractionated therapy: large toxic nodular
(1966) therapy (123) 38% cured by 1 treatment goiters with tracheal
2. Fractionated (none of these developed compression in some
therapy (34) hypothyroidism) cases. All of the cases
76% cured by two were unsuitable for
treatments. 9/123 (7.3%) surgery. Minimum
hypothyroid follow-up of 1 year
2. Fractionated therapy: 1. 3 deaths within
19/34 cured (the 30 days
remaining 15 patients 2. No deaths within
were given additional 4 months
radioiodine and were
ultimately cured)
4/34 hypothyroid
Neal (1965) 196 I131 therapy: 74.0% euthyroid
standard calculated 13.8% hypothyroid,
dose of 10,000 rad to 12.2% hyperthyroid
the gland
500 I131 therapy: 79.8% euthyroid
Calculated dose of 8.2% hyperthyroid
5000–8000 rad to the 12% hypothyroid
thyroid gland
Dunn and 1452 I131, 160 μCi/g thyroid I131: In patients followed for
Chapman tissue, 1391 patients 808/1391 (58%) euthyroid 10 years or more, the
(1964) I130, 681 μCi/g thyroid 365/1391 (26%) incidence of
tissue, 61 patients hypothyroid hypothyroidism rose to
96/1391 (9%) probably 43%
hypothyroid
I 130:
24/61 (39%) euthyroid,
27/61 (44%) hypothyroid,
6/61 (10%) probably
hypothyroid
Beling and 791 I131: At 1 year: 7.46% Hyperthyroidism
Einhorn Dose calculated to hypothyroid. During without demonstrable
(1961) give 6000–10,000 rad subsequent observation, goiter (298 patients)
to the gland approximately 3% Diffuse toxic goiter (218
developed hypothyroidism patients)
per year. At 7 years: Toxic nodular goiter
26.5% hypothyroid (167 patients)
2.2 Long-Term Follow-Up Studies

in Patients Treated with I131
for Hyperthyroidism
Total # of
Gronich 16,617 I131 (2829 patients) Mean follow-up of 7.27 years. No
et al. vs. thionamides association between RAI and risk of
(2020) (13,808 patients) overall cancer. Higher occurrence of
non-Hodgkin lymphoma in the RAI
group (7/2829 vs. 11/13,808), which
was statistically significant in the
univariate analysis, but failed to reach
statistical significance in the
multivariate analysis
Mizokami 117 I131: 3.6–29.8 mCi Median follow-up of 95 months. No Patients were 10–18 years
et al. (median 13.0 mCi) thyroid cancer or other malignancies old when treated
(2020) diagnosed
Ron et al. 35,593 I131, surgery or RAI was not associated with an Data from the Cooperative
(1998) antithyroid drugs, increase in total cancer deaths. RAI Thyrotoxicosis Therapy
alone or in was associated with an increased risk Follow-up Study
combination of thyroid cancer. An increase in cancer Patients in the group who
mortality was observed in the only received antithyroid
antithyroid drugs-only group drugs had the highest rate
of previous cancer
Safa et al. 87 I131: Follow-up of 5–24 years (mean Patients were 3–18 years
(1975) Dose, 2.9–31 mCi 12.3 + 3.5) of age when treated.
(mean 9.75 + 6.5) No deaths and no cancer or leukemia Major cause of goiter
were observed in patients or their regrowth was Hashimoto’s
offspring. Reproductive history and thyroiditis
health status of the progeny of
I131-treated patients were not different
from those of the general population
Hayek 30 I131 (28 patients) Average follow-up of 9.2 years. No Patients were 8–18 years
et al. I130 (2 patients) deaths and no evidence of cancer or of age when treated
(1970) leukemia. One female treated with I130
had an abnormal reproductive history
Saenger 36,000 I131 Incidence of leukemia in the two Data from the Cooperative
et al. (22,000 patients) groups did not differ Thyrotoxicosis Therapy
(1968) Surgery or Follow-up Study
antithyroid drugs
(14,000 patients)
Beling U, Einhorn J (1961) Incidence of hypothyroidism

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Long-term follow-up results in children and adoles- Viherkoski M, Lamberg BA, Hernberg CA et al (1970)
cents treated with radioactive iodine (131I) for hyper- Treatment of toxic nodular and diffuse goitre with
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in large toxic goitres. Acta Endocrinol 51(1):7–14 thyroid drugs in Graves’ disease: a meta- analysis
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doses of 131-I in treatment of thyrotoxicosis. Br Med 89(1064):20160418
J 1(5533):129 Waterfall NB, Glaser MG (1979) A study of the effects of
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Iceland. Acta Med Scand 198(1–6):309–314
Musculoskeletal Disorders
David Y. Mak and Philip Wong
Contents 16 Plantar Fibromatosis, Ledderhose

Disease 163
1 Aneurysmal Bone Cysts 105
17 Baker’s Cyst 165
2 Ankylosing Spondylitis 110
18 Thalassemic Arthropathy 165
3 Arthritis 116
3.1 Osteoarthritis 116 References 165
4 Rheumatoid Arthritis 116

5 Bursitis, Synovitis, and Tendinitis 119
5.1 Bursitis Historical Studies 122
1 Aneurysmal Bone Cysts
6 Desmoid-Aggressive Fibromatosis 126
7 Dupuytren’s Contracture 136 An aneurysmal bone cyst (ABC) is a benign bone
lesion that is frequently managed by surgical
8 Enthesopathy 138
curettage to minimize treatment-associated mor-
9 G
orham’s Massive Osteolysis bidities. Local recurrence occurs in approxi-
(Spontaneous Absorption of Bone,
Phantom Bone) 138 mately 20% of patients after intralesional
curettage (Mankin et al. 2005). En bloc resection
10 Giant Cell Tumor (Osteoclastoma) 140
and radiotherapy are used to reduce recurrences.
11 Hemophiliac Arthropathy 150 Resolution of the lesion is progressive and
12 Heterotopic Bone Formation 150 delayed when radiation is used. Lower doses are
suggested by the recent literature and seem indi-
13 Heel Spur (Plantar Fasciitis) 158
cated since they may lower the long-term risk of
14 Osteoblastoma/Osteoid Osteoma 160 carcinogenesis.
15 Pigmented Villonodular Synovitis
(Tenosynovial Giant Cell Tumor) 161
15.1 Radionucleotides 163
D. Y. Mak
Radiation Medicine Program, Princess Margaret
Cancer Centre, University Health Network,
Toronto, ON, Canada
e-mail: david.mak@rmp.uhn.ca
P. Wong (*)
Radiation Oncology, University of Toronto/Princess
Margaret Cancer Centre, Toronto, ON, Canada
e-mail: philip.wong@rmp.uhn.ca

Total # of
106

Elsayad et al. (2017) 10 EBRT with mean dose 28 Gy (range All patients (n = 7; 3 lost to follow-up) had Mean F/U 65 months (range
5–40 Gy) with mean fractional dose radiological response with persistent pain 12–358 months)
of 2 Gy (range 1–2 Gy) relief and no recurrent disease No >grade 3 acute or late toxicities with no
secondary malignancies
Zhu et al. (2017) 12 Radiotherapy alone (n = 9) or No recurrent disease Median 20.5 years (range 3–36 years)
postoperative radiotherapy (n = 3). No adverse reactions
Mean dose 30.15 Gy (range
20–60 Gy), in 1.5–2 Gy per fraction
Wang et al. (2014) 8 Radiotherapy alone (n = 4), mean No evidence of recurrence in any irradiated Mean F/U 44.5 months (range 12–96
dose 34 Gy (range 19.6–40 Gy) patient months).
Postoperative radiotherapy (n = 4), Mean visual analogue scale (pain) was No details provided about fractionation
mean dose 26 Gy (range significantly better (p < 0.01) at 6-month
800 cGy–40 Gy) follow-up
Wu et al. (2011) 8 Postoperative (4–6 weeks) Disease control: 3 patients developed local No patient had radiation myelopathy or
radiotherapy; total dose range recurrence at 12 (n = 2) and 14 months malignant transformation. Median F/U 31
30–50 Gy (n = 1). Remaining patients recurrence free months.
No details provided about fractionation
Kamikonya et al. 8-year-old 10 MeV photons 500 cGy × 4 Complete resolution No leg discrepancy or loss of motion with a
(1991) female 2-year follow-up
Maeda et al. (1989) 8-year-old 125 cGy × 4 Linac Excellent 3.5-year follow-up
female
Jereb and Smith 10-year-old 200 cGy × 10 Excellent Suggest below 3000 cGy, long-term risk
(1980) female not as great for carcinogenesis and late
effects
Marks et al. (1976) 3 Radiotherapy: 4000r (midline Recalcification with no evidence of Age range of the patients was 11–16 years.
dose)/18–20F/3.5 weeks. recurrence in all three patients at follow-ups All three lesions were in the pelvis
Megavoltage irradiation was used of 2–7 years
Delorit and Summers 1 Radiotherapy: 3800r (tumor dose) Objective improvement of the XI and XII Lesion of the sphenoid sinus. The patient
(1975) followed by surgical removal nerve palsies but no changes were evident on presented with bilateral VIth, IXth, Xth,
the cerebral arteriogram. It was then decided XIth, and XIIth palsies. Patient was 23
to surgically remove the tumor. Six-month years of age
follow-up showed almost complete
resolution of the cranial nerve palsies
D. Y. Mak and P. Wong
Clough and Price 21 1. Curettage (19 patients, 16 also Recurrences (include treatment of both initial Minimum follow-up of 2 years
(1973) had a graft) and recurrent lesions):
2. Resection (5 patients) 1. 11/19
3. Radiotherapy plus curettage (2) 2. 0/5
4. Radiotherapy (2) 3. 0/2
4. 0/2
Prakash et al. (1973) 4 Surgical removal followed by a 3/4 moderately quick recovery of spinal cord All four were aneurysmal bone cysts of the
course of radiotherapy 800–2000r function which was maintained at follow-ups spine. Age range 17–48 years
of 1.5–7 years. One case was quadriplegic at
presentation and showed only partial

neurological recovery
Biesecker et al. 44 Primary treatment: Recurrences: Fifty-nine percent of the lesions were of
(1970) 1. Curettage (44) 1. 26/44 (60%) long bones. Data based on total treatment
2. Radiotherapy, 1200–3200r 2. 1/4 (including recurrences) showed a
(tumor dose) (4) 3. 1/7 significant difference in the recurrence rate
3. Cryosurgery. 4. 0/8 between radiation therapy and curettage
4. Block excision 5. 0/1 and between cryosurgery and curettage.
5. Amputation There was no significant difference
between radiation therapy and cryosurgery
Stevens and Weaver 1 Excision followed 1 month later by Patient free of pain and no complaints at Lesion of the spine. Patient was 18 years of
(1970) radiotherapy, 2000r 3-month follow-up age
Dabska and 13 1. Surgical excision (radical or 1. Condition satisfactory at 1–7-year Age range: 14–44 years
Buraczewski (1969) partial) (4) follow-up.
2. Excision or curettage plus 2. Condition satisfactory at 1–3-year
radiotherapy (3500–5000r). (4) follow-up.
3. Radiotherapy alone (2500–4428r) 3. Condition satisfactory at 4–10-year
(4) follow-up in three patients. Malignant
change requiring amputation in one patient
Nobler et al. (1968) 33 1. Surgery initially (26) Recurrences: 20/33 (61%) were 19 years of age or
2. Surgery for recurrence (5) younger. Sixty percent of the lesions were
3. Irradiation for recurrence (6) 1. 8/26 ( 31% ) ïü in the pelvis and lower extremities
ý10/31( 32% )
4. Irradiation for recurrence (5) 2. 2/5 ( 40% ) þï
5. Irradiation plus surgery (1).
3. 1/6 (16% ) ü
Details of radiotherapy: 1200– / ( 8% )
ý112
3160r (tumor dose)/9–18 days with 4. 0/5 þ
250 kV, 100 kV, Co60 5. 0/1
(continued)
107
Total # of
108

Slowick et al. (1968) 13 1. Resection (4) Recurrences: 12/13 were 20 years of age or younger
2. Curettage plus bone grafts (5) 1. 0/4
3. Radiotherapy, 1400–2000r 2. 1/5
(tumor dose) (4) 3. 0/4
All had lesions of the spine
Tillman et al. (1968) 95 1. Curettage alone or in Recurrences: All were cases of aneurysmal bone cyst.
combination with cautery and/or 1. 0/6 with radiotherapy. 8/28 without Sarcoma developed in 3/95. Irradiation had
graft (34) radiotherapy been used in all three cases. Authors
Six patients also received 2.0/11 suggest reservation of radiotherapy only for
radiotherapy 3. 1/6 with radiotherapy. 2/9 without cases in which surgical removal is not
2. Resection and graft (11) radiotherapy feasible
3. Excision (9) plus radiotherapy (6) 4. 0/1
4. Amputation plus radiotherapy (1) 5. 1/1
5. Radiotherapy (1) Overall results:
2/14 recurred with radiotherapy
11/48 recurred without radiotherapy
Granjobst and 1 Radiotherapy: 2470r (tumor dose) At presentation, the tumor was massive and Lesion of the left superior pubic ramus.
Hopkins (1967) followed by excision and highly vascular. Following irradiation, the Patient was 17 years of age. The irradiation
curettement 2 years later growth of the tumor ceased and calcification was not curative, but it may have reduced
increased. Following surgery, the cavity in the vascularity of the tumor, making the
the pubis and ischium healed. There was no surgical approach less hazardous
recurrence at 8-year follow-up
Parrish and Pevey 3 Excision followed by radiotherapy. 2/3 cysts healed and there was no evidence All were lesions of the vertebral column.
(1967) Tumor dose: 1500r/10F/12 days or of recurrence at 2-year follow-up. In one Age range of 13–30 years
3000–3800r/20–25F/4–5 weeks patient, the cyst recurred and was excised
twice. There was filling in the sacral mass
and no recurrence 6 months following the
last excision
Verbiest (1965) 2 Surgery alone (1) or radiotherapy Recovery from neurological disturbances in Both cases were lesions of the spine. Age
followed 1 year later by surgery (1) both patients. No evidence of recurrence at 15 and 44 years
but doubt as to the exact diagnosis 6-year and 21-year follow-up
Donaldson (1962) 6 1. Excision followed by 1. No evidence of recurrence at 3- and 6-year Age range 2–19 years
radiotherapy 1150–2250r (tumor follow-up.
dose) post-op (2) 2. 3/4 no recurrence at 3–7-year follow-ups.
2. Excision or curettage and Recurrence in one patient following
packing (4) curettage and packing treated by excision
No recurrence at 4-year follow-up
MacCarty et al. 11 1. Excision or curettement (4) 1. No recurrences at 3-month–8-year All were lesions of the spine, sacrum, or
(1961) 2. Excision or curettage followed by follow-up. occipital bone. Age range 10–25 years
radiotherapy (6) 2. 5/6 patients well at 3–18-year follow-up.
3. Radiotherapy followed 2 months 3. Healing at the site of graft, but extension
later by surgical removal (1) into lamina and spinous process. Lesion was
again removed. Patient well at 3-year
follow-up
Godfrey and 5 1. Excision (4) 1. Recovery in all four patients Age range 3–43 years
Gresham (1959) 2. Curettage and grafting followed 2. Gradual recalcification and no further
by radiotherapy (1500r tumor dose) extension of the cyst at 1-year follow-up

(1)
Beder et al. (1957) 7 1. Radiotherapy only (2) 1. Complete recovery in one case. Age range 13–28 years
2. Radiotherapy plus surgery (5) Satisfactory recovery with some residual
In both groups, radiotherapy was deformity in the other case
usually 1200–1600r in air/2 weeks. 2. 4/5 complete recovery. 1/5 satisfactory
Two courses 2 months apart were recovery (less than complete regression at
given 2-year follow-up)
Cruz and Coley 20 1. Surgery alone (13) Follow-up of 4 months–32 years: Age range 9–44 years
(1956) 2. Radiotherapy alone (5). One 1. 13/13 cured
received radium treatment 2. 5/5 cured
3. Surgery plus radiotherapy (2). 3. 2/2 cured
Radiotherapy: 500–2320r total air
dose
Taylor (1956) 3 1. Surgery alone (1) 1. Patient free from symptoms and no Age range 4–16 years
2. Biopsy and partial removal recurrence at 1-year follow-up
followed by radiotherapy (1) 2. Patient free from symptoms and no
3. Radiotherapy alone (1) recurrence at 3-year follow-up
3. Patient free from symptoms and no
recurrence at 9-year follow-up
(continued)
109
110 D. Y. Mak and P. Wong
2 Ankylosing Spondylitis aberrations are also reported. It is our opinion

that the use of radiation in the management of
Ankylosing spondylitis is an autoimmune chronic ankylosing spondylitis should be under protocol
inflammatory disorder that affects the vertebral design and require institutional approval. Based
and sacroiliac joints. With time and progression, on the available historic data, there are no con-
the condition causes chronic back pain, limita- temporary indications for routine radiotherapy.
tions in mobility, and respiratory restrictions Current treatments for ankylosing spondylitis are
(NICHD Definition Code C84564). Perhaps a aimed at reducing symptoms and maintaining
classic in risk/benefit ratios is the contrast of the spinal flexibility through the use of nonsteroidal
report of Brown and Doll (1965), showing a 9.5 anti-inflammatory drugs (NSAIDs). TNF inhibi-
times incidence of leukemia in irradiated patients, tors had been shown to be efficacious for patients
with the report of Radford et al. (1977), showing who progress on or who cannot tolerate NSAIDs.
the severity of the underlying spondylitis without However, TNF inhibitors are contraindicated in
irradiation. More recent updates and reviews patients with active infection or a high risk of
have emphasized the increased mortality among infection, advanced heart failure, lupus, multiple
irradiated patients and confirmed the increased sclerosis, and cancer. More recently, patients who
leukemia risk occurring in the first 5 years after progressed on TNF inhibition have benefited
treatment as well as an increased risk of solid from secukinumab, a monoclonal antibody
tumors occurring 10–20 years after treatment. against interleukin-17 (Baeten et al. 2015). The
Included in the solid tumors are gastrointestinal accompanying list of references will serve the
cancers, lung cancer, myeloma, spinal cord reader with appropriate caution. There has been
tumors, bone and soft tissue sarcomas, and basal no new literature evaluating the role of radiother-
cell carcinomas. Other morbidities including cat- apy in ankylosing spondylitis since 2002.
aracts, retroperitoneal fibrosis, and chromosomal
Total # of
Author, year patients Technical details Time/dose Results Complications/comments
Calin and 376 treated Questionnaire with Deep X-ray. Details not No significant difference at review (2 years 22% of UK patients with
Elswood patients controls matched for provided after treatment) in: use of NSAID, total hip ankylosing spondylitis received
(1989) (subset sex and age replacement, symptoms, pain, stiffness, deep X-ray. Treated group could
analysis of Retrospective study uveitis, ability to work. Spinal mobility and have had more severe disease than
100 treated overall function in a measurement scale were control group. Data do not support
patients, and poorer for those irradiated (5.5 vs. 4.8; the use of deep X-ray except for
100 matched p < 0.0001) exceptional cases
controls)
Darby et al. 14,106 1935–1954, United At least one course of X-ray Mortality 28% greater among irradiated Maximal proportional increase in
(1987) patients Kingdom treatment. Details not patients than general population. Leukemia mortality occurred 10–12.4 years
provided deaths threefold increase, greatest for after treatment. Total mortality and
AML. Colon cancer deaths 30% increased. organ-specific mortality reported
Nonneoplastic conditions, 51% increase in
deaths, due to disease itself not the treatment
Darby et al. 14,111 1935–1954, United Details not given for Spondylitis had mean bone marrow dose twice Significant excess risks observed
(1985) patients Kingdom. Ankylosing ankylosing spondylitis that of bomb survivors (335 rad vs. 125 rad) for cancers of esophagus, stomach,
spondylitis patients patients. Minimum of 100 but 1/2 the risk of leukemia. For solid tumors lung, ovary, multiple myeloma,
compared with atomic rad given to atomic bomb in spondylitis, excess risk increased with age lymphoma, spinal cord, and nerve
bomb survivors survivors at exposure and time since exposure tumors
Schmitt 250 Treated with 224Ra 10 weekly injections of 200 Treated patients had subjective improvement No secondary malignancies.
and between 1952 and electrostatic units of 224Ra with decreased need for anti-rheumatoid and “Authors” recommend 224Ra as
Ruckbeil 1980 compared with (equivalent analgesic drugs. Blood and X-rays showed no having no higher risks than
(1983) ankylosing dose = 25–28 μCi/week). change. common drug treatments
spondylitis patients Total skeletal dose was 56 22 of 169 patients had children. Of 32
treated without 224Ra rad children, 2 had cerebral palsy and diabetes
from Germany insipidus
Wick and 1531 Treated with 224Ra 10 weekly injections Three malignant tumors of skeleton among
Gössner since 1950 in intravenously, each of those receiving less than 90 rad (0.4–0.6
(1983) Germany. Ankylosing 28 μCi. Cumulative dose of expected). 2 of the 3 tumors were of the bone
spondylitis patients 56 rad to the marrow-free marrow
treated with 224Ra are skeleton
compared with 267
spondylitis patients
not treated with
X-rays or
radionuclides. Mean
follow-up is 26 years
(continued)
111
112
Total # of
Smith and 14,111, Given a single course Mortality from all causes 66% greater than in Risk of cancer related to age at the
Doll (1982) 1935–1944, of X-ray treatment, at general population. Mortality from leukemia, time of treatment. Patients older
United least mean bone fivefold excess. Nonleukemia cancers, 62% than 55 years have higher risk than
Kingdom marrow dose was 347 excess in radiated sites. Leukemia risk is those less than 25 years.
rads greatest the first 5 years after treatment. Other No dose-response relationship is
cancer risk 9–20 years after treatment. Risk of demonstrated for leukemia risk,
cancer not in irradiated site was 20% greater perhaps because higher doses
than expected sterilize more leukemia cells
Smythe Review article— 500 r 64% improvement Concludes that with better
(1979) compares anti- 1000 r 15 of 17 improved anti-inflammatory medication,
inflammatory therapy, radiotherapy is seldom required. If
radiation, used, the short-term benefits need
physiotherapy, to be balanced with the long-term
surgical therapy risks
Belcourt 533 1948–1960 60% of patients treated with 20% improved There were significantly more
(1973) 1960–1971 radiotherapy 20% deteriorated cases of leukemia in the first period
11% of patients treated with 50% improved than in the second
radiotherapy 10% deteriorated
Sinclair 195 Not specified 157 patients received full
(1971) treatment to whole spine
and sacroiliac regions
Kinsella 50 200 kV, HVL 1 mm 1000r depth dose/15 days to Spinal joints: 88–96% clinically active lesions. Acute leukemia and aplastic
et al. Cu, FSD, 50 cm. epiphyseal and Peripheral joints: 23–33% clinically active anemia (2 patients). The disease
(1966) Eight ports: costovertebral joints lesions showed no evident decrease in
15 × 15 cm for each followed by a second activity in the irradiated patients
sacroiliac joint. course 3–4 months later. based on the patient’s subjective
10 × 15 cm port for Third course given 6–8 response, physical exam, lab tests,
each lumbar, thoracic, months later and radiological indices.
and cervical area Symptomatic relief of spinal
arthralgia for approximately 2
years in those patients able to
tolerate the initial radiation
sickness
Parry 170 Deep X-ray therapy Not given X-ray therapy: (42%) progression of the
(1966) or physiotherapy and disease
drugs (salicylates and Physiotherapy and drugs: 31/130 (24%)
oxyphenylbutazone) progression of the disease
Mason 250 Radiotherapy or drug Radiotherapy:
(1964) treatment 93/189 (49%) marked symptomatic relief 3
(phenylbutazone and months later
oxyphenylbutazone) 13/23 (57%) marked symptomatic relief 1–5
years later
57/166 (34%) marked symptomatic relief
more than 5 years later
Drug therapy:
46/61 (75%) marked symptomatic relief 3
months later
33–43 (77%) marked symptomatic relief 1–5
years later
12/18 (67%) marked symptomatic relief more
than 5 years later
Sambrook 108 250 kV, HVL, Average incident dose to Stage I patients (44):
(1963) 1.5 mm Cu the spine of 1400r. Average 83% symptomatic relief
incident dose to peripheral 75% objective improvement (range of motion)
joints of 900r 50% needed further treatment within 10 years
Fulton 573 None given 1. High dose: 5-year results Aplastic anemia (1)
(1961) Four methods of (a) 2000r or more/2 weeks High dose: Subacute myeloid leukemia (1)
irradiation: to skin of back 112/149 (75%) Improvement rate at 5 years in
(a) Trunk baths (b) 750r single treatment to Stage I improved. 108/194 (56%) high-dose group was twice that of
(b) Whole spine a local area Stage II improved. 76–157 (49%) low-dose group
(c) Limited portion of 2. Low dose: Stage III improved.
spine (a) 1500r or less 2 weeks to Low dose:
(d) Isolated joints of skin of back 6/18 (33%)
muscle insertions (b) Long-protracted Stage I, improved
treatment 13/33 (39%)
Stage II, improved
5/22 (23%)
Stage II, improved
Wilkinson 200 200–500 kV, 1 mm 1000–2000r (total skin Relief of pain: 134/200 good, 42/200 Only 43% of patients were not
and Cu plus 1 mm A1 dose) 3 weeks to each of moderate symptomatic relapse of 67.4% at requiring regular analgesics within
Bywaters filtration FSD 5 cm 4–5 spinal fields 1 year, 90% at 10-year follow-up 1 year after treatment. Myeloid
(1958) leukemia (1)
Possible activation of pulmonary
tuberculosis
(continued)
113
Total # of
114
Howard 455 200 kV, HVL, 2.3 mm 1500r skin dose/8–10F. Two Stage I patients (138): 198 (43%) relapses
(1957) Cu, FSD, 50 cm fields treated daily. Total 115/138 (83%) good, 19/138 (14%) moderate 144 retreated at a later date
Fields: length of treatment 34 Stage II patients (156):
1 sacroiliac field: weeks 121/156 (78%) good, 32/156 (20.5%)
16 × 12 cm or moderate
10 × 15 cm. 3 spinal Stage III patients (103):
fields: 80/103 (77%) good
16 × 15 cm or 11/103 (10%) moderate
6 × 20 cm Stage IV patients (58):
45/58 (78%) good
11/58 (19%) moderate
Ward 93 Deep X-rays. 17 Not given 39/93 well
(1955) patients received 28/93 moderately well
more than one course
of treatment
Hair (1954) 118 Deep X-rays. Spine is Not given 91 patients symptom free after 5 years; 27
treated in sections, the patients still under treatment
sacroiliac joints first
Sharp and 275 250 kV, HVL 1.6 mm 1500r (skin dose) 178/275 (65%) much improved. Extensive haemochromatosis 2 1/2
Easson Cu, FSD, 50 cm 10F/10 weeks. Whole spine 68/275 (25%) slightly improved years after treatment (1).
(1954) and sacroiliac joints treated Reactivation of pulmonary
through rectangular tuberculosis
applications, 7.5 cm in
width. Peripheral joints
treated through parallel
opposing fields
Desmarais 70 220 kV, 15 ma, 1 mm High voltage: Marked improvement: 7/14 (50%) Technique a Similar results in cases where
(1953) Cu plus 1 mm A1 (a) 500r (spine, hip) 13/17 (76%) Technique b treatment was directed to areas
filters, HVL, 1.5 Cu, (b) 1000r (spine, hip) 7/19 (89%) Technique c other than the spine
FSD, 50 cm or (c) 1500 (spine) 2000 (hip). 3/11 (27%) low voltage
140 kV, 5 ma, .25 mm Spine and sacroiliac joints 4/9 (44%) controls
Cu plus 1 mm A1 divided into 5 fields; each
filtration, HVL, field received
7.5 mm A1, FSD, approximately 300r/2F/l
25 cm week
Total length of course: 4–6
weeks. Low voltage:
300r skin dose/6F/3 weeks.
Fields: 10 cm strip over

sacrum and sacroiliac joints
Toone 29 190 kV, 20 ma, 600r/4F to each field 19/29 (67.9%) good-excellent results
(1949) 0.5 mm Cu plus 1 mm
A1 filtration, FSD
50 cm. Four fields:
(a) Sacroiliac, 20 × 20
(b) Lumbar, 10 × 15
(c) Dorsal, 10 × 15
(d) Cervical, 10 × 10
Hilton 47 Small field, local Not given 7/47 completely free of pain.
(1943) irradiation 38/47 improved (free from continuous pain)

Smyth 52 200 kV, .5 mm Cu 600r/3F/5 days. Three 37/52 (72%) significant improvement, 12/13 (92%) with early disease
et al. plus 1 mm A1 series given at monthly subjective. improved significantly.
(1941) filtration, HVL .9 mm intervals. No more than 26/52 (50%) significant improvement, Leukopenia in 3 patients—dosage
Cu, FSD 50 cm 300r/series over female objective reduced
pelvis
Hare 35 150–200 kV, 20 ma, 300r to each portal. 80% relief of pain. 33/35 are now able to work
(1940) .25–.5 mm Cu plus Repeated in 3 weeks if
1 mm Al filtration. necessary
FSD, 50 cm. 6 portals
(300 sq. cm each)
115
3 Arthritis researchers observed 45% objective improve-

ment for placebo compared to 43% objective
Arthritis is an inflammatory process affecting improvement for radiation. No statistical differ-
joints. There are many causes of arthritis includ- ence in the chi square test was observed between
ing infection, autoimmune processes, degenera- external irradiated and nonirradiated patients.
tive processes, and trauma. Symptomatically, the Similarly, Valtonen conducted a double-blind
inflamed joint results in pain, swelling, warmth, trial in 104 patients who had painful degenerative
erythema, and/or reduced range of motion and inflammatory musculoskeletal conditions
(Unified Medical Language System - Concept and observed 59% improvement in irradiated
Unique Identifier C0003864). patients, compared to 65% improvement in the
Three studies critically examined radiation for placebo group. Plenk also reported no difference
arthritis, comparing control nonirradiated between treated and non-treated patients with
patients to irradiated patients, and observed no calcific tendonitis of the shoulder. A randomized
differences between the patient groups. Goldie controlled trial completed by Mahler et al. did
et al. reported in a double-blind study of 399 not find a signal of benefit from the use of radio-
patients equivalent subjective and objective therapy given as 6 Gy/6 fractions.
results for tendonitis, arthritis, etc. These
3.1 Osteoarthritis
Author, Total # off
year patients Treatment Results Notes
Mahler 55 Randomized, double-blind, sham- No difference in F/U 3 months
et al. controlled trial. 6 Gy/6 fractions every symptoms or postintervention.
(2019) other day vs. sham RT inflammatory signs Knee osteoarthritis
only
4 Rheumatoid Arthritis The potential for different responses in light

of the nature of the disorder must be considered
Rheumatoid arthritis is an arthritic condition when viewing the most recent experience with
related to a chronic, systemic autoimmune disor- total lymphoid irradiation. Total lymphoid irra-
der that affects the synovial membranes and diation (TLI) treatment, similar to that applied in
articular surfaces beyond the axial skeleton. Due Hodgkin’s disease, is an experimental therapy yet
to the erosive nature of the disorder, joints to be fully defined. The rationale for TLI therapy
become severely damaged, which leads to pain is the potential reduction of total lymphocyte
and loss of function. The etiology of the disorder numbers (CD3+) and the increased repopulation
is unknown but typically associated with rheuma- of suppressor T-lymphocytes (CD8+) versus
toid factor and anti-citrullinated protein antibod- (CD4+) helper cells. Although immunologic sup-
ies. More women than men get rheumatoid pression is established, the antibody titer to rheu-
arthritis (Unified Medical Language System - matoid factor was not altered by TLI, nor was the
Concept Unique Identifier C0003873). antibody pneumococcal polysaccharide. The
Musculoskeletal Disorders 117
finding in rheumatoid arthritis that autoantibody methotrexate plus low-dose glucocorticoid, fol-
was not reduced despite arthritis reduction lowed by the use of multiple lines of disease-
implied that cellular immunity was necessary for modifying antirheumatic drugs (DMARDs) such
arthritis progression and that autoantibody was as sulfasalazine, hydroxychloroquine, and
not an integral part of the important pathogenic molecularly targeted agents (Smolen et al. 2016).
mechanisms. Finally, it has been interesting to note no increased
An additional and inadequately explored potential for leukemia, unlike experience with
question remains whether the ideal dose of TLI orthovoltage radiation in a younger population
has been established definitively. In a random- with ankylosing spondylitis. A review by Rackoff
ized study from Ireland published in 1986, 750 and Feldman recalls that TLI is not for rheuma-
rad was as adequate in remission induction as toid arthritis (Rackoff and Feldman 1997).
2000 rad. Additional differences in total dose of Practitioners are recommended not to treat with
TLI, e.g., 2000 rad (Stanford) versus 3000 rad TLI.
(Harvard), seem to imply a more sustained immu- The inflamed joint of rheumatoid arthritis can
nosuppression with the lower dose. This, com- be not only painful but also disabling.
bined with increased infection and complications Nevertheless, external beam radiotherapy aimed
following the higher dose, raises the issue of at painful joint has not been effective (Graninger
whether repeated modest doses of TLI distributed et al. 2005). More recent studies evaluating the
over longer fractional courses, quite unlike pres- use of radionuclides showed signs of safety and
ent schedules, might not prove superior. While efficacy that need to be validated. The use of
immunosuppression remains the main manage- radiotherapy in the treatment of rheumatoid
ment goal for rheumatoid arthritis, current means arthritis cannot be recommended at this time,
to achieve immunosuppression include the use of outside of clinical trial settings.
Total #
Author, year offpatients Treatment Results Notes
Graninger 6 20 Gy (2 Gy/fraction) over Ineffective. Trial RCT with F/U planned for 2, 6,
et al. 2 weeks to single inflamed stopped for ethical and 12 weeks from RT start
(2005) joint with concurrent reasons
disease-modifying
antirheumatic drugs
(DMARDs) and NSAIDs.
Sham irradiation to
contralateral joint as
control. F/U 3 months
postradiation
Radionucleotide studies
118
Total #
Author, of
Amini 16 Intra-articular installation Excellent/good, moderate, and poor responses in 56.5%, 8.7%, and 34.8%, Follow-up at 1, 3, 6, and 12 months
et al. of 32P respectively post-procedure
(2020) WOMAC, VAS, and HAQ pain scores all showed significant improvement
(p < 0.05)
Mu 120 Randomized to: ACR20 response rate of treatments 1, 2, and 3 were 15.62%, 42.04%, and Follow-up at 14 days post-therapy
et al. 1. Oral meloxicam 48.78%, respectively, with a significant difference between groups 1 and 2
(2018) tablets (p < 0.05) but not between groups 2 and 3
2. IV 99Tc-MDP No difference in the incidence of adverse events between all 3 treatment
3. Both 1 and 2 arms
Liepe 99 Radiosynovectomy with Pain response by 10-step VAS showed no difference between the different F/U at 1, 3, 6, and 12 months
et al. either: radionucleotides 16% had transient pain flare and swelling
(2011) 1. 90Y silicate (n = 68) Compared to corticosteroids, pain relief at 12 months was more durable that resolved 1 month post-procedure
2. 32P colloid (n = 15) with radiosynovectomy (p < 0.05)
3. Re-188 Tin colloid
(n = 16)
Compared to 20–40 mg
corticosteroid (n = 46)
dos 58 Patients randomized to Using a VAS, there was no significant difference between treatment arms F/U at 1, 4, 12, 32, and 48 weeks
Santos either: with regard to joint pain, swelling, morning stiffness, flexion/extension, post-intervention
et al. 1. Intra-articular knee circumference, or degree of improvement (Likert scale and
(2009) injection with 40 mg percentage)
triamcinolone alone More adverse effects when adding 153Sm at 1 week postintervention, but
2. 153Sm with mild and transitory, with no significant difference at any other timepoint
triamcinolone
injection
Soroa 36 1. 32P colloid (n = 26). Significantly improved median remission rate for 32P compared to F/U at 3, 6, and 9 months
et al. 2. Rifampicin (n = 10) rifampicin (p < 0.025)
(2005)
Lee 21 Radiosynovectomy with Pain as measured by VAS significantly improved at 12 months F/U at 1, 3, 6, 9, and 12 months
et al. 188Re-tin-colloid (p = 0.0001), with improvements in joint swelling (100%), pain (86.3%), post-administration.
(2003) and tenderness (63.6%) No significant adverse effect
5 Bursitis, Synovitis, induced by injury and may result in a repair

and Tendinitis response that includes the formation of fibrosis
and granulation tissues (NCI Thesaurus Code:
Bursitis, synovitis, and tendinitis consist of pain- C97141).
ful inflammation of the bursa, synovium, and Bursitis, synovitis, and tendinitis are inflam-
tendon, respectively. The bursa is a flat, fluid- matory discomforts having ill-defined natural
filled sac found between a bone and a tendon or histories. Three older randomized studies (Goldie
muscle. Bursitis seems to be associated with the et al. 1970a; Plenk 1952a, b; Valtonen et al. 1975)
overuse of a joint or trauma and often affects the conclude that there is “no benefit” derived from
hips, shoulders, elbows, and feet (NCI Thesaurus treatment (Goldie et al. 1970a, b; Plenk 1952a, b;
Code: C94407). The synovial membrane is a Valtonen et al. 1975). Although recent evalua-
layer of connective tissue that lines a joint, such tions involving large number of patients report
as the hip, knee, ankle, or shoulder. Synovitis potential benefits of radiotherapy, none of these
refers to the inflammation of this membrane reports have compared radiotherapy to other
(NCI Thesaurus Code: C50766). The tendons treatment modalities or placebo. High-quality
are flexible connective tissues that connect the evaluation of radiotherapy in comparison to non-
muscles to the bones. Tendonitis refers to the radiotherapy treatments is needed before it can be
inflammation of the tendons, which could be considered a standard treatment modality.
Total # off
120

Hautmann et al. 138 elbows (124 3.0 Gy/6 (n = 13), 6.0 Gy/6 Pain: Median NRS scores were 7, 4, 0, and 0 Epicondylitis humeri
(2019a, b) patients) (n = 124). F/U at 6 weeks, 12 and prior to RT and 6, 12, and 24 weeks post-RT,
24 months respectively, p < 0.001
Juniku et al. 598 3.0 Gy/6 (n = 34), 5 Gy/10 Pain: Median VAS scores were 7, 5, 4, and 1, Median F/U of 38 months (range 29–47).
(2019) (n = 564) prior to RT, immediately after, 12 weeks and 38 Significant responses (p < 0.001) were
months post-RT, respectively, p < 0.001 observed immediately after RT and at 38
months
Better pain response in enthesopathies
than arthrosis
Micke et al. (2018) 703 6.0 Gy/6 or 6.0 Gy/12 treated on Pain: Median VAS scores were 6.6 and 4.5 prior Median F/U 33 months (range 3–60)
LINAC (n = 254) or orthovoltage to and immediately after RT, respectively. 4% No long-term improvement for
(n = 449) and 35.5% of patients were pain free gonarthrosis.
immediately after and 33 months post-RT, Conditions treated include calcaneodynia,
p < 0.001 achillodynia, painful gonarthrosis, painful
trochanteric bursitis, and painful shoulder
syndrome
Kaltenborn et al. 74 Hips (60 3.0 Gy/6 or 6.0 Gy/6 Pain: Subjective patient-reported pain responses Mean F/U was immediately after, 3, and
(2017) patients) showed that 2/3rds of patients experienced 18 months post-RT
partial or complete symptom remission
(particularly nocturnal pain) at 3 months
post-RT.
Disease control: Remission was achieved in
72%, 70%, and 72% immediately after, 3
months, and 18 months post-RT
Micke et al. (2017) 166 6.0 Gy/6 or 6.0 Gy/12. Median Pain: Median VAS scores were 6.4 and 4.5 prior Median F/U 29 months (range 3–39).
F/U 29 months to and immediately after RT, respectively. 3.6% Conditions treated include calcaneodynia,
and 30% of patients were pain free immediately achillodynia, painful gonarthrosis, and
after and 29 months post-RT, p < 0.001 painful trochanteric bursitis
Miszczyk et al. 50 6 MV photons, 1 Gy/fraction, up Pain: Complete pain relief was achieved in 5%, F/U immediately after the treatment and
(2015) to 6 Gy 18.8%, 22.2%, 35.7%, 45.8%, 57.9%, 50%, and at 1, 2–3, 4–6, 8–12, 15–18, 19–24, and
40% immediately after and at 1, 2–3, 4–6, 8–12, 26–30 months posttreatment. Partial pain
15–18, 19–24, and 26–30 months posttreatment, relief, joint mobility, joint edema, joint
p = 0.02–0.04 for each time point hyperthermia, and analgesic use reported
in paper
Objective pain responses only assessed in
12 patients
Total # off
Ott et al. (2015) 112 Randomized to orthovoltage Pain: Median VAS scores for 3.0 Gy/6 treatment For achillodynia:
3.0 Gy/6 or 6.0 Gy/6 over 3 arm were 55.7, 38.0, 35.5, and 11.2 before, Median F/U 24 months (range 11–56).
weeks, with re-treatment with immediately after, 6 weeks, and 2 years post-RT, Comprehensive pain scores (CPS) also
same regimen if insufficient pain respectively. Median VAS scores for 6.0 Gy/6 reported, in addition to Visual Analogue
response treatment arm were 58.2, 30.4, 30.9, and 15.3 Scale (VAS)
before, immediately after, 6 weeks, and 2 years
post-RT, respectively
No difference between the 2 dose regimens
Ott et al. (2014) 312 Randomized to orthovoltage Pain: Median VAS scores for 3.0 Gy/6 treatment For painful shoulder syndrome:
3.0 Gy/6 or 6.0 Gy/6 over 3 arm were 56.8, 38.2, 33.0, and 27.9 before, Median F/U 35 months (range 11–57).
weeks, with re-treatment with immediately after, 6 weeks, and 3 years post-RT, Comprehensive pain scores (CPS) also
same regimen if insufficient pain respectively. Median VAS scores for 6.0 Gy/6 reported, in addition to Visual Analogue
response treatment arm were 53.2, 34.0, 23.7, and 32.1 Scale (VAS)
before, immediately after, 6 weeks, and 3 years
post-RT, respectively
Ott et al. (2013) 112 Randomized to orthovoltage Pain: Median VAS scores for 3.0 Gy/6 treatment For achillodynia:
3.0 Gy/6 or 6.0 Gy/6 over 3 arm were 55.7, 38.0, and 35.4 before, Comprehensive pain scores (CPS) also
weeks, with re-treatment with immediately after, and 6 weeks post-RT, reported, in addition to Visual Analogue
same regimen if insufficient pain respectively. Median VAS scores for 6.0 Gy/6 Scale (VAS)
response treatment arm were 58.2, 30.4, and 30.9 before,
immediately after, and 6 weeks post-RT,
respectively.
Ott et al. (2012) 199 Randomized to orthovoltage Pain: Median VAS scores for 3.0 Gy/6 treatment For painful elbow syndrome:
3.0 Gy/6 or 6.0 Gy/6 over 3 arm were 59.6, 32.1, and 27.0 before, Comprehensive pain scores (CPS) also
weeks, with re-treatment with immediately after, and 6 weeks post-RT, reported, in addition to Visual Analogue
same regimen if insufficient pain respectively. Median VAS scores for 6.0 Gy/6 Scale (VAS)
response treatment arm were 55.7, 34.4, and 23.5 before,
immediately after, and 6 weeks post-RT,
respectively.
Adamietz et al. 115 shoulders 3.0 Gy/6 fractions over 2–3 weeks, 82% achieved pain relief at 18 months Median F/U 18 months
(2010) (102 patients) with a second course of treatment
6 weeks apart
Niewald et al. 141 Heterogeneous: 89% received Pain: Pain relief achieved in 56%, 69%, and Median F/U at 4.5 months and 3.9 years
(2007) 6 Gy over 3 weeks with photons, 73% of patients directly after, at 4.5 months, post-RT
with others receiving 4–8 Gy with and 3.9 years post-RT
Co-60, electrons, and orthovoltage (continued)
121
5.1 Bursitis Historical Studies
122
Total # of
Author, year patients Bursitis historical studies Time/dose Results Complications/comments
Milone and 136 250 kV, 15 ma, 1.95 mm 450(air) 3/F/3 days alternating between the Immediate results (3 Roentgenographic evidence of
Copeland (1961) Cu filtration, FSD, 50 cm. 3 portals days–4 weeks). tissue calcification was present
Field size: 10 × 10 cm3 Acute cases: 49/54 in all cases.
fields: anterior, posterior, (90.7%) favorable Acute: a few days to 2 weeks.
and lateral response. Subacute: 3–8 weeks Chronic:
Subacute cases: 3 or more months
11/14(78.6%) favorable
response.
Chronic cases:
15/24 (62.5%) favorable
response
Chronic cases with acute
exacerbation:
34/44 (77.3%) favorable
response
Arner et al. (1958) 80 None given 700r/10 days Late results Calcific deposits in all cases
Acute cases:
45/45(100%) good
results.
Chronic cases:
11/12 (91.7%) good
results.
Chronic with acute
exacerbation:
15/23 (65.2%) good
results
Schoss and Otto 153 140 kV, 15 ma, 0.25 mm 450 (air)/3F/5 days to each port. Anterior Immediate results 64.4% of those X-rayed
(1955) Cu plus 1 mm Al and posterior ports treated on alternate days Acute cases: showed calcium deposits
filtration. HVL 84/88 (95.4%) favorable Acute: 10 days or less
0.5 mm Cu, FSD 50 cm. results Chronic: longer than 10 days
Two 15 × 15 cm ports to Chronic cases:
the shoulder, one anterior, 56/65 (86.1%) favorable
one posterior results
King and Mahaffey 456 200 kV, 0.5 mm Cu plus 125–150r (air) may be repeated in 24–48 h. 83% completely relieved 8% involvement of sites other
(1953) 1 mm Al filtration, FSD Third treatment, if necessary, given 2–3 of pain and function than the shoulder
50 cm days following second treatment reestablished, 14%
Field size: 10 × 15 to Fourth treatment may be given 1 week later recurrences

15 × 20 cm
Total # of
Garber (1952) 111 200 kV, 0.5 mm Cu plus 450r (air)/3F/1 week, repeated for chronic 92.8% good result 57.6% had calcification
1 mm A1 filtration, FSD cases
50 cm.
One portal, 10 × 10 cm to
the anterior-lateral aspect
of the shoulder
Kratzman and 200 kV, 15 ma, 450–600r(air)/3–4F/3–4 days Immediate results (220 87.3% of those X-rayed
Frankel (1952) 0.5 mm Cu plus 1 mm Al cases) showed calcification
filtration, FSD 50 cm Acute cases: Acute: 1 week or less
98.1% favorable results. Subacute: 1–4 weeks

Subacute cases: Chronic: Longer than 4 weeks
95.6% favorable results.
Chronic cases:
75.5% favorable results.
Late results 80.6%
Mann (1952) 52 200 kV, 0.25 mm Cu 75–150r/treatment; usually 2–6 treatments 47/52(90%) satisfactory No calcium in only 2 patients
are given. Treatments given every 2–5 days response
Plenk (1952a, b) 38 400 kV, 5 mm, 2 mm Cu 450r(air)/3F/5 days 15/21 definite Calcification in 82% of
plus 1 mm Al filtration, improvement. Controls controls, 81% of the treated
HVL, 3.75 mm Cu, FSD (no treatment). 15/17 group
70 cm definite improvement
Field size: 10 × 10 or
10 × 15 cm
Witt and Titterington 50 1. Deep therapy (37 225–450r/3F/l week. Additional treatments Acute cases (17): Acute: less than 1 month
(1951) patients): 200 kV, 15ma, (75–150r) at weekly intervals up to a total 96.2% good results Chronic: longer than 1 month
1mm Cu plus 1 mm Al of 6 treatments may be given Chronic cases (33):
filtration 85.8% good results
2. Superficial therapy (17 Little significant
patients): 100 kV, 5 ma, difference between the
l–3 ma Al filtration deep and superficial
Portal size: therapy
100–225 sq cm
Steen and 300 200 kV, 0.5 mm Cu plus 600r(air)4F/4 days to the point of maximum 251/300 (83.6%) 68% of those X-rayed had
McCullough (1951) 1 mm Al filtration, FSD tenderness favorable results evidence of calcium
50 cm A further course given if necessary
Field size: 10 × 10 cm
O’Brien (1950) 200 kV, 0.5 mm Cu plus 200r/treatment 4–6 treatments 4 days apart The majority reported
1 mm Al filtration, FSD relief after the second
50 cm treatment
123
Field size: 15 × 15cm

(continued)
Total # of
124

Lattomus and 235 1. 120 kV, 10 ma, 4 mm 1. 400R/2–4F 1. Low voltage: Acute: Up to 1 week
Hunter (1949) Al filtration at FSD 30 cm 2. 600R/3F/5 days Acute cases: 41/45 Subacute: Up to 2 months
2. 200 kV, 15 ma, 0.5 mm (90.0%) good results Chronic: longer than 2 months
Cu plus 0.5 mm Al Subacute cases:
filtration, FSD 50 cm 50/61 (82%) good results
Field size: circular, 10 cm Chronic cases: 43/77
diameter (55.8%) good results
2. Deep therapy:
Acute cases:
4/4 good results
6/10 (60%) good results
Chronic cases:
18/38 (47.4%) good
results
Hodges and Boyer 200 120 kV, 0.5 mm Cu plus 600–800r/3–4F/3–4 days divided between Acute cases:
(1948) 0.5 mm Al filtration, FSD, anterior and posterior fields. If the response 89% relief of symptoms.
25 cm is slow, an additional 250r to the posterior Subacute cases:
cervical spine is given 75% relief of symptoms
Allen (1947) 40 200 kV, 10ma, 0.5mm Cu 400–800r to each of the 3 fields or 27/40 (76.5%) complete
plus 1mm Al filtration, 800–1000r/4–5F/4–5 days to one field relief of pain
FSD 50cm. Field size: 31/40 (77.5%) complete
three 3.5 × 7 cm or one 10 use of arm
× 10 cm
Gelber (1947) 15 180 kV, 0.5 mm Cu plus 800–1000r (air)/4–5F of this total dose, 13/15 showed
1 mm Al filtration, FSD approximately 300r is given anteriorly, 300r improvement
80 cm posteriorly, and 200–300r laterally
Pohle and Morton 33 200 kV, 0.5 mm Cu plus 450 (air)/3F/3 days or 600r (air)/3F/5 days 80% moderate to
(1947) 1 mm Al filtration, HVL complete relief
1.05mm Cu, FSD 50 cm,
or 400 kV, 1.75 mm Cu
filtration, HVL 2.4 mm
Cu, FSD 50 cm
Young (1947) 87 180 kV, 8 ma, 0.5 mm Cu 150r (air)/treatment Acute cases: 14/16 43.6% incidence of
plus 1 mm Al filtration, 1–4 treatments were given complete relief calcification
FSD 50 cm Subacute cases: 19/23
Portals: 10 × 15 or complete relief
15 × 15 cm Chronic cases: 16/48
(33%) complete relief

Total # of
Klein (1946) 100 125–200 kV, 5–7 ma, FSD 750–1000r/6–8Fx2/7–14 days Acute cases (61): 69% Acute:
30–40 cm reduction in calcification less than 1 month
Subacute cases (11): Subacute:
36% reduction in 1–2 months
calcification Chronic: longer than 2 months
Chronic cases (28): 32%
reduction in calcification
Nobre and de Araujo 18 Not specified 150–200r/treatment. 6 or more treatments 15/18(85%) favorable
Cintra (1944) with 2–3 days between treatments results
Baird (1941) 18 200 kV, 18 ma, 1 mm Cu 300r (air) 16/18 completely cured Calcification present in all
plus 1 mm Al filtration, Repeated at intervals of 3–4 weeks if cases
FSD 50 cm angled over necessary Acute: 9 cases
the anterior-lateral portion Subacute: 5 cases
of the shoulder Chronic: 5 cases
Pendergrass and 120 kV, 5 ma, 5 mm Al 300–450r/3F/# of days 64% benefitted
Hodes (1941) filtration or 0.25 mm Cu
plus 1 mm Al filtration,
FSD, 30–40 cm or 50 kV,
0.2 mm Cu filtration, FSD
3–5 cm
Weinberg (1940) 180 kV, 4 ma, 0.5 mm Cu 100–250r given 2–3 times weekly. Total of 15/24 complete relief
plus 1 mm Al filtration, 3–12 treatments given
FSD 50 cm. Field size:
10 × 10 cm to 15 × 20 cm
(continued)
125
6 Desmoid-Aggressive desmoid-aggressive fibromatosis (Mendenhall

Fibromatosis et al. 2005; Gronchi et al. 2003; Janssen et al.
2017). Radiation therapy in doses of 5000–
Aggressive fibromatosis or desmoid is a locally 6600 cGy is often utilized in the definitive or
aggressive benign connective tissue neoplasm. adjuvant settings. Several studies reported overall
This tumor may arise from any part of the body, response rates of 40–60%. Larger studies sug-
thereby causing symptoms according to the anat- gested that the 5-year local control of aggressive
omy involved. Somatic mutations in the CTNNB1 fibromatosis following definitive radiotherapy is
gene (3q21) encoding beta-catenin have been 63–82%, with perhaps better control when
found in about 85% of sporadic cases. Patients >5000 cGy is given. Studies evaluating the effi-
with familial adenomatous polyposis (FAP) are at cacy of adjuvant radiotherapy in reducing local
risk of developing intra-abdominal fibromatosis. recurrences have produced mixed results. This
Histologically, the tumor is made up of elongated may have to do with confounding factors in stud-
spindle-shaped well-differentiated myofibroblasts, ies in which radiotherapy was often prescribed
collagenous stroma formation, and an infiltrative for patients with positive surgical margins or
growth pattern (NCI Thesaurus Code: C9182). recurrent diseases. Regression may occur from 8
Following surgical excision alone, local recur- months to 2 years following treatment.
rences occur in about 20–40% of cases of
Bishop et al. (2020) 109 RT only, 85 Median dose of 56 Gy (56–75) Local control at 5 and 10 years for RT only Median F/U 95 months (1–509)
RT + surgery for RT alone, and 50.4 Gy was 65% and 62%, respectively, and 77 1% (n = 3) of patients receiving RT
(50–66) for RT + surgery and 75% for RT + surgery developed RT-associated malignancy
Single-modality treatment (RT or surgery) at a median time of 15.1 years
was inferior to combined RT + surgery (10.8–17), all of whom was treated
(p = 0.04) for desmoid of the trunk
de Bruyns et al. Up front, 8 with RT 88% received 50 Gy or higher PFS for RT only (up front and salvage) at 2 Median F/U 77 months
(2020) only, 11 with (2 Gy/fraction) years was 86% (95% CI 72–100). No statistical significance in
neoadjuvant RT, 13 with Recurrence rates were 27.3% (n = 3) and neoadjuvant or adjuvant RT in
adjuvant RT. 7.7% (n = 1) for up-front neoadjuvant RT up-front setting.
In the salvage setting, 15 and adjuvant RT, respectively, and 25% No significant RT-related toxicities
with RT only, 4 with (n = 1) and 0% for salvage neoadjuvant RT or secondary malignancies
neoadjuvant RT and 6 and adjuvant RT, respectively, at median
with adjuvant RT F/U 77 months
Seidensaal et al. 40 (44 treatments) Median dose 54 Gy (39.6–66) Local PFS 76.4% and 63.8%, overall PFS Median F//U 32 months (1–153).
(2020) treated with photons (n = 28), 72.3% and 58.4%, and OS 97.4% and No toxicity >G3 other than 1 severe
protons (n = 15), and carbon ions 97.4% at 3 and 5 years GI bleed
(n = 1)
Bishop et al. (2019) 209 Primary RT (median 56 Gy, LC for RT alone 71% and 59%, and for Median F/U 98 months (1–509)
50–75) and combined-modality CMT 80% and 79%, at 5 and 10 years,
RT with surgery (median 50.4 Gy, p = 0.01.
44–67) However, LC at 5 years for RT only 43%
(<30 years old) vs. 75% (>30 years old),
p = 0.001
Luo et al. (2019) 31 Split-course RT with median 99 PFS 90% and 71.3% at 3 and 5 years. Median F/U 60.4 months (2–187).
days (81–122) in between with Interval time <100 days vs. >100 days Acute and long-term complications
median 3969 cGy (22) (2999– prognostic for PFS, HR 11.544, p = 0.047 in 29% and 9.7%
4305) for first phase and
2495 cGy/14 (1982–3039) for
second
Niu et al. (2019a) 34 Adjuvant RT median dose 60 Gy EFS 74.6% (RT) vs. 13.3% (no RT) at 3 Median F/U 38 months (2–146).
(44–68) delivered with 3DCRT years, p < 0.001 No serious RT complications
and IMRT
Niu et al. (2019b) 30 Primary RT, median dose 60 Gy Complete response and partial response in Median F/U 50.5 months (2–126).
(50–66.6) in 2 Gy fractions 16.7% and 40% of patients No serious toxicities >G2 skin
reaction
(continued)
127
128
Bates et al. (2018) 101 50–55 Gy in 1.8–2 Gy/fraction OS 98% and 95%, and local control 82% Median F/U 14.3 years (0.3–41.5)
with cobalt RT, photon (3DCRT and 78%, at 5 and 10 years, respectively.
and IMRT), and electron Once-daily fractionation improved LC
(90%) compared to twice-daily
fractionation (73%), p = 0.008
Choi et al. (2018) 47 (8 primary RT, 39 Median dose 54 Gy (48.6, 50.4, 15% recurrence at 60 months. CTV >5 cm Median F/U 60 months
adjuvant) and 54 Gy for R0, R1, R2 (p = 0.039) and dose >45 Gy (p = 0.049)
resection, respectively) improved non-recurrence
Hong et al. (2018) 50 (43 primary, 7 Median dose 56 Gy (30–58.8) for 22% with progressive disease at median 41 Median F/U 51 months
adjuvant) primary and 50.4 Gy (48–56) for months (12–113) 1 patient with RT-induced
adjuvant malignancy 20 years after RT
Ning et al. (2018) 27 receiving adjuvant 44–52 Gy Improved RFS with RT at mean F/U 6.6 Mean F/U 6.6 years (2–11.8).
RT years (p = 0.012) No RT-related complications
Sparber-Sauer et al. 15 EBRT or electron median EFS 80% at 3 years Median F/U 5.05 years (0.25–14.88)
(2018) 58.5 Gy (48–60) either after
resection or systemic therapy
Van Broekhoven et al. 35 54–56 Gy/28–30 fractions Complete response in 11% at 12, 17, 26, Median F/U 44 months (24–62).
(2018) and 29 months. Partial response in 31%, at Only 1 patient with >3 RT-related
15.5 months (4–56). 46% with stable toxicity
disease and 0% disease progression at 44
months (24–62)
Wirth et al. (2018) 21 receiving adjuvant Dose and fractionation not No significant effect of RT on local Median F/U 119 months
RT specified recurrence
Moding et al. (2017) 4 Concurrent imatinib and RT Pain: Relief in median of 2.5 months Median F/U 8 months (3–18).
50–54 Gy in 25–28 fractions (0–11) G1-2 RT toxicity; 1 patient with
Disease control: Radiological reduction in avascular necrosis of humoral head
tumor volume 49% (8–93%)
Santti et al. (2017) 41 Median 50 Gy (20–63) with 55% objective response rate at 14 months Median F/U 7 years (0.8–17)
median 2 Gy/fraction Significant dose-response relation for
definitive and postoperative RT (p = 0.002)
Tsagozis et al. (2017) 17 adjuvant RT; 14 No dose or fractionation provided No significant effect of RT or Median F/U 38 months (1–290)
adjuvant chemoRT chemotherapy on local control
Ergen et al. (2016) 20 Median dose 60 Gy LC 80% and 69% at 2 and 5 years, Median F/U 77.5 months (28–283)
respectively Most common G1–2 skin toxicity. 1
LC at 5 years significantly improved if patient with RT-induced sarcoma
dose >54 Gy (p = 0.023)
Ma et al. (2016) 19 55 Gy adjuvant RT (no Recurrence rates for surgery alone vs. Median F/U 125.6 months (11–524)
fractionation described surgery + RT were 48.1% and 88.9%,
respectively
Matsumine et al. 5 Intraoperative electron 25–50 Gy 80% disease free at F/U, remaining 1 Median F/U 56 months (27–67)
(2016) patient alive with disease
Cates (2015) 15 Adjuvant RT; no dose or Adjuvant RT of the primary tumor only Median F/U 3.6 years (2.5
fractionation provided (not first recurrence) was associated with months–22.3 years)
an increased risk of second recurrence
(p = 0.032)
Houdek et al. (2014) 27 Adjuvant RT; no dose or Time to recurrence increased with adjuvant Median F/U 9 years (2–30)
fractionation provided RT (2.6 vs. 1.6 years), but disease-free
interval at 5 years (57%) unchanged
Kucuk et al. (2014) 12 Adjuvant RT 44–54 Gy/25–30 Trend toward lower recurrence with RT Median F/U 70.1 months (13–276)
fractions (p = 0.06). Recurrence in 8% (RT) vs. 42%
(no RT)
Zeng et al. (2014) 43 38–66 Gy (93% adjuvant, 4.7% No significant effect of RT on local Median F/U 54 months (1–299)
neoadjuvant, 2.3% both) recurrence
Karabulut et al. (2013) 13 50–60 Gy Adjuvant RT had no significant effect on
recurrence
Keus et al. (2013) 44 56 Gy/28 LC 81.5% at 3 years Median F/U 4.8 years
Kriz et al. (2012) 52 Definitive RT median 55 Gy Overall, LC 79%, no difference in Median F/U 44 months (8–62)
(55–65) and adjuvant RT median definitive vs. adjuvant RT
dose 50 Gy (60–50 Gy), in
1.8–2 Gy fractions
Prodinger et al. (2013) 14 Adjuvant RT 50–60 Gy Adjuvant RT had no effect after a first Average F/U 64 months
recurrence, but improved 5-year RFS after
second recurrence (89% with RT vs. 25%
no RT, p = 0.015)
Shin et al. (2013) 24 Adjuvant RT 38–70 Gy in 19–35 Median recurrence from surgery was 32 Mean F/U 82 months
fractions months (4–123, adjuvant RT) vs. 14
months (4–46, no adjuvant RT), p = 0.026
Soto-Miranda et al. 16 Adjuvant RT 44.8–67.6 Gy No statistical significance, although trend Median F/U 4.8 years (<1–14)
(2013) (n = 13 adjuvant, n = 1 for improved 5- and 10-year RFS with
neoadjuvant, n = 7 adjuvant RT (p = 0.35)
brachytherapy). No fractionation
schedule
Turina et al. (2013) 4 Brachytherapy 14–35 Gy 50% with complete remission and 50% Median F/U 19 months (13–25)
with partial remission at 19 months
129
(continued)
130
van Broekhoven, et al. 54 Adjuvant RT >50 Gy in 2 Gy No significant effect on local recurrence at Median F/U 38 months (1–222)
(2013) fractions 5 years
Colombo et al. (2012) 6 Combined modality with CMT with IORT (n = 2) 50% (n = 1) alive Median F/U 2.3 years (0.2–17.9)
surgery ± chemo with IORT with NED. CMT with RT (n = 4) (n = 2)
(n = 2) and RT (n = 4) alive with NED, % (n = 2) alive with
disease
Mullen et al. (2012) 36 Adjuvant RT 44.8–67.6 Gy. No No significant effect on local recurrence at Median F/U 40 months
fractionation schedule 14 months
Gluck et al. (2011) 41 Definitive RT and adjuvant RT, No significant difference between surgery Median F/U 3 months
median 55.8 Gy (50–68.4) in alone, RT alone, and adjuvant RT on LC at
1.8–2 Gy fractions 3 years
Hentati et al. (2011) 6 Adjuvant RT 54–62 Gy delivered LC in 83.3% at median F/U of 26 months Median F/U 26 months (1–83)
with Co60 (n = 5) and photons
(n = 1)
Husain et al. (2011) 24 Adjuvant brachytherapy (median LC 88.2% at F/U. No difference between Mean F/U 4.28 years
43 Gy, 30–50, n = 6), EBRT brachy and EBRT
(median 49.8 Gy, 44–62, n = 10),
or both (n = 3)
Rutenberg et al. 30 35–64.8 Gy in 1.8 Gy daily OS and LC 96% and 55% at 15 years Median F/U 13.3 years (0.4–29.9)
(2011) fractions or 1.2 Gy BID fractions LC 79% (dose >55 Gy) vs. 30% (<55 Gy), 40% with grade 3–4 complications
p = 0.02
Roeder et al. (2010) 30 Intraoperative electrons (median LC 82% at 3 years Median F/U 32 months (3–139)
dose 12 Gy) with 25 patients
receiving additional EBRT
(median dose 45 Gy, 36–54)
Rudiger et al. (2010) 34 Definitive (n = 17) and adjuvant RFS for adjuvant RT was 83.6% at 5 and Median F/U 51 months (8–172)
RT (n = 17) with EBRT median 10 years
50.4 Gy in 28 fractions Definitive RT showed complete response
20%, partial response 20%, and stable
disease in 53%
Francis et al. (2009) 30 Neoadjuvant RT 30 Gy/10 No significant effect on RFS at 5 and 10 Median F/U 45 months (0.2–149.5)
years
Huang et al. (2009) 25 Adjuvant electrons 45–55 Gy. No No significant difference on RFS at 5 and Median F/U 102 months (7–256)
fractionation schedule 10 years
Jabbari et al. (2009) 15 Post-chemo salvage RT (n = 2) NED: Median F/U 75.7 months (16–162)
GTR (+ margin) adjuvant EBRT – Post-chemo salvage RT 50% (n = 1)
(n = 3) and salvage RT (n = 4) – GTR (+ margin) adjuvant EBRT
GTR (− margin) adjuvant salvage 100% (n = 3) and salvage RT 100%
HDR (n = 1) (n = 4)
STR adjuvant EBRT (n = 2) and – GTR (− margin) adjuvant salvage
salvage (n = 1) HDR 100% (n = 1)
– STR adjuvant EBRT 0% (n = 2)
Kumar et al. (2009) 8 Adjuvant RT for recurrence. No No significant effect on local recurrence F/U range 1–10 years
dose or fractionation provided

Stoeckle et al. (2009) 23 Adjuvant RT median dose 50 Gy No significant effect on recurrence at Median F/U 123 months (3–482)
(20–60) 14–17 months, compared to other 78% (n = 18) had RT-related
treatment strategies functional impairments
Bonvalot et al. (2008) 13 Adjuvant RT mean 50 Gy No significant difference on RFS at 3 years 1 patient developed angiosarcoma
(45–60). No fractionation compared to surgery alone within the radiation field 11 years
schedule later
Guadagnolo et al. 115 Definitive RT (median 56 Gy) 5- and 10-year local control of 75% and Median F/U 10.5 years
(2008) and combined modality with 74%. No significant difference between
surgery (median 50.4 Gy) definitive RT and combined modality
Baumert et al. (2007) 68 Surgery vs. adjuvant RT median PFS 95% and 93% (adjuvant RT) vs. 84% Median F/U 6 years (1–44)
55.6 Gy (3.4–68), mixture of and 62% (surgery only) at 5 and 10 years,
photon, Co60, electron, brachy, p = 0.0028
and orthovoltage Dose >50 Gy (HR 0.6, p = 0.028) and
fractions >2 Gy (HR 0.59, p = 0.036)
improved PFS
Guney et al. (2007) 7 Definitive and adjuvant RT 3 disease free, 3 alive with disease, 1 Median F/U 15.5 months
median dose 51 Gy passed away 15 days after RT
Seinfeld et al. (2007) 4 Adjuvant fractionated RT At 57 months, all patients alive with local Median F/U 57 months
50–54 Gy control achieved in 3 patients, and the last
having recurrence outside of RT field
Seinfeld et al. (2006) 3 Adjuvant RT 50–54 Gy in 25–30 75% recurrence free at F/U Median F/U 48 months (11–67)
fractions
Sharma et al. (2006) 19 (15 adjuvant RT, 4 Median 60 Gy (9–70) (10 with RT only: Recurrence (n = 2) at 3 and 29 42% with RT had severe moist
RT only) Co60 gamma rays, 6 with months. Remaining disease free at 40 and desquamation (all received >60 Gy)
electrons, 2 with photons, and 1 44 months
with both photon and electrons) Adjuvant RT: LC of 86% at 24 months, but
no significant effect of adding RT
Buitendijk et al. 2 Adjuvant RT 57.6 and 59.4 Gy No recurrence at F/U F/U at 82 and 47 months
131
(2005)
(continued)
132
Abbas et al. (2004) 19 Adjuvant RT, no dose Recurrence rate of 27% (no RT) vs. 0% Median F/U 53 months (2 weeks–21
fractionation provided (RT), p = 0.0027 years)
Chew et al. (2004) 16 Primary or adjuvant RT; no dose Median time to recurrence 12 months (no Median F/U 12.5 years (3–30.9)
or fractionation schedule RT) vs. 52 months (primary or adjuvant
RT), p = 0.004. No difference between
primary and adjuvant RT
Duggal et al. (2004) 12 Adjuvant RT median 57.5 91.6% with no disease at F/U; 1 patient Median F/U 47 months (11–114)
(10–64 Gy) alive with recurrence
Baliski et al. (2002) 13 Neoadjuvant chemoRT with 85% (n = 11) disease free at 71 months Median F/U 71 months (22–109)
doxorubicin and 30 Gy/10,
followed by resection
Schulz-Ertner et al. 28 Adjuvant RT (n = 26) and LC 73% at 5 years Median F/U 46 months (13–108)
(2002) definitive (n = 2) with median
dose 48 Gy (36–60)
Sorensen et al. (2002) 28 Adjuvant RT, no dose For extra-abdominal tumors only, RFS Median F/U 8 years (1–27)
fractionation provided 77% (RT) vs. 57% (no RT) at 5 years
Zlotecki et al. (2002) 72 EBRT median 52 Gy in 1.8 Gy LC 83% at 5 years Median F/U 6 years
daily fractions or 1.2 Gy BID
fractions
Acker et al. (1993) 40 4960–5620 cGy 15/16 or 94% local control 52-month follow-up, 14 n.e.d., one
died with disease, one lost to
follow-up
Karakousis et al. 26 10 patients irradiated 96% control, no amputations
(1993) 4000–5000 cGy
192
Zelefsky et al. (1991) 38 Iridium 75% were recurrent, Control rate 5 years, 75%. 5 years after Surgery plus 192iridium implant
50% 8 cm or greater, 79% close salvage surgery 95%. 30/34 excellent result
surgical margin, 16% gross
residual disease
McCullough et al. 29 5000 cGy some b.i.d. 83% control. Five failures at the edge of
(1991) field or gross residual disease
Tsukada et al. (1991) 8 8 chemo, 3 irradiated Chemo 2 CR, 1 PR, 5 died. Radiation no Not consistent with general radiation
response, dose too low therapy dose and experience
Mirabell et al. (1990) 26 and 24 26 surgical 9/26 surg. cases recurred. Five-year control 80% relapse-free survival. Individual
24 surgery plus radiation rate 68%. Ten primary control 100%. 5/14 approach in treatment philosophy
10 primary radiation failed
14 recurrent plus radiation
22–75 Gy
Sherman et al. (1990) 45 50 Gy min, 7–27 Gy boost 10 local control, 4 failures Recommend 50–55 Gy
31 local controls, 77%
Bataini et al. (1988) 26 45–50 Gy, 1–15 Gy boost 22/26 n.e.d. Complete remission up to 2 years
Stockdale et al. 29 Surgery plus radiation. Dose 22 n.e.d. 7 relapses orthovoltage less than Resolution took up to 21 months
(1988a, b) 35–64 Gy 50 Gy
Keus and Bartelink 21 40 Gy plus 20 Gy boost Local control 19/21
(1986) 5-year 90% disease free
Assad et al. (1986) 14, Median age 31 Surgery and brachytherapy plus 92% (11/12) local control rate with 3/14 had wound healing problems
years; 11 females, 3 external beam boost of minimum of 2-year follow-up after brachytherapy; brachytherapy
males 3000–5000r should be initiated no longer than
72 h after therapy
Khorsand and 19 Varied according to 3 groups: Disease-free survival in initial therapy Doses of XRT not provided
Karakousis (1985) Median age 39 years; 10 with Gardner’s syndrome, group:
females, 9 males recurrent and initial therapy 9/9 (100%) from 1 to 13 years
Leibel et al. (1983) 19 Radiation 5000–5500r 72% relapse-free survival, 5–11-year Median follow-up 8 years. Local
Median age 27 years; 11 follow-up. control not related to the amount of
females, 8 males 4 of 6 had recurrences at margin of field. disease. VAC chemotherapy used for
1 had in-field recurrence radiation salvage
Greenberger et al. 9 Radiation 3000–6800r 8 of 9 controlled Follow-up 2–8 years
(1981)
Abadir (1976) 1 6000r/31F/45 days (Co60) to Tumor completely disappeared. Recurred 1 The desmoid tumor was located in
tumor year later coincident with cystosarcoma the upper anterior abdominal wall.
3900r/13F/40 days (10 Mev) to phyllodes of the breast The 2 tumors eventually became
right upper anterior abdominal confluent, and the patient expired
wall
Suit and Russell 6 7500r/54F/78 days (details of one All patients are alive and free from disease Authors recommend: 6000r/7–8
(1975) case only) after 2–8 years weeks.
All were extra-abdominal desmoids
Hill et al. (1973) 4 5100–6100r/30–34F/42–53 days 3 patients are free from disease at 2-year Extra-abdominal tumor (3).
(Co60), 4 Mev or 6 Mev follow-up. Tumor has regressed to 20% of Abdominal tumor (1)
its original size in the fourth patient
Gaches and Burke 1 2900r (superficial X-rays)/5 Tumor regressed noticeably after first Both were abdominal wall desmoids
(1971) weeks. treatment but had grown considerably 2
Second course of 2300r 1/2 years later. Mass did not regress after
second course
1 Excision only Free from disease at 8-month follow-up
Cole and Guiss (1969) 2 Wide surgical excision. 1/2 complete regression of recurrence All were extra-abdominal desmoids
Recurrences treated by following radiotherapy (patient is clinically
radiotherapy free of disease at 3-year follow-up)
(continued)
133
134
2 Surgical excision. Recurrences Patients are clinically free of disease at 4

treated by further excision and in years and 12 years later
1 case, forequarter amputation
Rosen and Kimball 1 1800r/2 weeks Tumor contained for 2 years. Large Both were extra-abdominal
(1966) mediastinal mass (from untreated desmoids
intrathoracic portion of original tumor)
was noted
1 Surgical excision. Recurrence Second recurrence treated with forequarter
treated with wide end block amputation
resection
Masson and Soule 34 Surgery alone (22 patients) No recurrence in 5/18 4 lost to follow-up. All were
(1966) extra-abdominal tumors
Surgery plus irradiation (8 No recurrence in 3/8 All were extra-abdominal tumors
patients). Radium interstitially,
250 kV X-ray or Co60
Irradiation alone (4 patients) No recurrence in 1/4 All were extra-abdominal tumors
Benninghoff and Excision followed by 2000– Regression of the tumor in all cases. No Abdominal tumor (1). Extra-
Robbins (1964) 4000r/3–4 weeks. recurrences 2–7 years later abdominal tumor (3)
(In 1 case, recurrence after
radiotherapy was followed by 2
weeks of prednisone therapy)
Soule and Scanlon 560r(air) 1 week: 4 weeks later, 6 1/2 years following the last X-ray Extra-abdominal desmoid
(1962) 610r/4 days to the same fields. 3 treatment an undifferentiated fibrosarcoma
weeks later, 660r to the same was found in the center of the recurrent
fields (130–200 kV, HVL desmoid
1.183.5 cm). This was followed
in 3 months by 600r/6 days to the
same area plus 600r (single dose)
to 2 new portals (200 kV, HVL
1.18 mm Cu)
Gonatas (1961) 1 2600r through various portals Regression of tumor. At 12-year follow-up, All were extra-abdominal desmoids
tumor was no larger than before
Surgical excision Recurrence in 1/5
Musgrove and 7 Radium and/or X-rays (no details No recurrence in 5/7 All were extra-abdominal desmoids
McDonald (1948) given)
Pack and Ehrlich 17 Excision 4/17 recurrences. All recurrences All were abdominal wall tumors.
(1944) responded to radiation therapy except 2. In 3 cases of malignant transformation
1 of these, the patient did not appear for
follow-up until the tumor had progressed
considerably
3 High-voltage roentgen or radium Tumor was satisfactorily controlled
element pack therapy. All were
inoperable cases
Recurrences of the above cases Surgery alone (for last recurrent tumor): 6
treated by surgery and/or patients have had no further recurrences

radiation for 2–21 years
Radiation alone (for last recurrent tumor):
5 patients have had no further recurrences
for 3–26 years.
Surgery and radiation (for last recurrent
tumor): 1 patient had no recurrence for 26
years
135
7 Dupuytren’s Contracture important contractures. Collagenase injections are

an additional treatment of some contractures caus-
Palmar fibromatosis is a genetically associated ing <30 degrees of finger flexion. Following the
disorder characterized by the growth of myofi- above interventions, the rate of relapse over 5
broblasts and collagen deposition at the metacar- years is 25–55% (Interventional Procedures
pophalangeal (MCP) joints and the proximal Guidance 2016). The availability of the treatment
interphalangeal (PIP) joints and palmar fascia of varies between countries. A phase 3 randomized
the hands. Whereas early growth of this benign trial is ongoing to compare patients’ quality of life
disease results in the formation of subcutaneous following collagenase injection vs. limited palmar
nodules and bands, continued growth eventually fasciectomy (clinicaltrials.gov NCT02725528).
leads to flexion contractures that prohibits the Several series with long-term follow-up suggested
extension of fingers (NCI Thesaurus Code: that radiotherapy is well tolerated when given
C3469). alone or postoperatively. These series observed
The natural evolution of the disorder varies good patient satisfaction and reported responses
from patient to patient as not all nodules or bands and stabilization of the disorder in a 75–83% of
grow to cause contractures. Surgical management patients, with 30 Gy in 10 fractions seemingly
consisting of surgical fasciectomy or needle apo- being more efficacious than 21 Gy in 7 fractions
neurotomy is the mainstay treatment of hands with (Seegenschmiedt et al. 2001).
Total # of
Zirbs et al. 206 32 Gy over 8 weeks with Improved symptoms Median F/U 40 months
(2015) 50 kV photons in 45%.
Local control in 80%
Grenfell and 6 15 Gy/5 with 6 MeV or Subjective reduction Median F/U 38.5 months
Borg (2014) 9MeV electron twice with a in pain in 50% and (29–61).
6-week break in between lesions reduced in Limited fatigue and
size in 83% erythema
Betz et al. (2010) 135 15 Gy/5 with 120 kV 66% long-term Median F/U 13 years
orthovoltage × 2 with 6–8 reduction in burning/ (2–25).
weeks in between itching/pressure/ Minor toxicities and no
tension RT-induced malignancy
59% stable disease,
10% improved, 31%
progressed
Seegenschmiedt 129 RCT of orthovoltage 120 kV At 12 months:
et al. (2001) 15 Gy/5 delivered twice, 8 15 Gy/5 × 2: 56%
weeks apart vs. 21 Gy/7 regressed, 37%
delivered within 2 weeks stable, 7%
progression.
21 Gy/7: 53%
regressed, 38%
stable, 9%
progressed.
Overall treatment
failure rate at 1 year
of 8%
Keilholz et al. 153 120 kV, 20 mA 2 mm Al, 92% stable at 3 At 5 years, 77% had no
(1996) patients, 5 × 3 Gy 2 courses. Total months. disease progression
96 30 Gy 75% objective
reported improvement at 3
(59%) months
(continued)
Total # of
Orlando et al. 128 1. Radical fasciectomy (23 1. 69% good-very Average follow-up of 2.3
(1974) patients) good results. years.
2. Partial fasciectomy (96 2. 72% good-very Complications in 128
patients) good results operations: wound
separation (8), Loss of
flap (8), hematoma (6),
primary infection (2)
Quetglas (1972) 80 Aponeurotomy of both the 1/80 recurrence.
fibers of the palm and the Total recovery
fingers usually at 3–6
months
McFarlane and 86 Limited fasciectomy, some 70/86(80%) good
Jamieson (1966) radical results. 10/86 (13%)
fair results
Webb-Jones 40 Radical fasciectomy 32/40 (80%) clear of Complications:
(1965) recurrence or Hematoma (1).
extension at 3 years, Oedema (11).
8 months Digital nerve injury (3).
Delayed wound healing
(3)
Finney (1955) 43 X-ray applicator 15/25 (60%) good
Palmar mold covering the functional results
palmar fascia and adjacent
tissues or grip cylinder.
Surface dose of 300r in 7–8
days
Medium-voltage X-ray 8/18 (44.4%) good
therapy (140 kV, 5 ma, HVL functional results
5.7 mm Al) 1500r in 3
fractions in 5 days
Skoog (1948) 2 Deep X-ray therapy (no 1 case—treatment
technical details given) given post-op—
lesion regressed.
1 case—radiation as
primary treatment—
deformity progressed
Beatty (1938) 10 100 kV, 5 ma, 1–2 mm Al 7/10 improvement
filtration, HVL .11–.14 mm with loss of pain,
Cu FSD 30 cm. 100–200r reduction of palmar
(air) × 3–4 at weekly nodes, and relief of
intervals contracture
8 Enthesopathy derness. One large series of close to 600 patients

suggested that 3–5 Gy in 0.5 Gy fractions was
Enthesopathy is a disorder affecting the site of associated with pain reduction. Further study
attachment of tendons or ligaments to the bones. would be needed to define the potential benefit (if
This entity is associated with injury or overuse any) of radiotherapy vs. standard of care or
leading to pain, inflammation, and localized ten- placebo.
Total # of
Juniku 598 3.0–5.0 Gy/0.5 Gy Pain by VAS: 7.0 (pre-RT) vs. 5.0 (post-RT), Median F/U 38
et al. fractions p < 0.001. Better with enthesopathies than months (29–47)
(2019) arthrosis.
No dose differences
9 Gorham’s Massive Osteolysis needed. The histopathologic findings reveal

(Spontaneous Absorption abnormal proliferation of endothelial lined capil-
of Bone, Phantom Bone) laries or sinusoidal channels of vascular or lym-
phatic origin. It may take the form of angiomatosis,
Spontaneous resorption of bone, either mono- or which generally is not progressive, or Gorham’s
polyostotic, is rare, and the etiology is unclear. disease which is progressive and results in func-
The disease is locally aggressive involving tional deformity. Both surgery and radiotherapy
resorption of regional bone and occasionally may be effective. The best results from radiother-
adjacent soft tissues. It most commonly affects apy appear to be with definitive treatment to
the shoulder girdle and pelvis. Occasionally, it involved areas in 1.8–2.0 Gy fractions to doses of
undergoes spontaneous regression, but more 40–45 Gy (Unified Medical Language System—
commonly surgery and/or radiation therapy are Concept Unique Identifier C0029438).

Liu et al. 4 Zoledronic acid with LC in 50% at F/U Median F/U 14
(2016) RT 40 Gy in 2 Gy months (6–24)
fractions
Hu et al. 6 30.6–57 Gy LC in 67% at 14 months Mean F/U 14
(2013) months
Brodszki 2 15 Gy/10 over 2 weeks Disease free at 2 years
et al. (2011) with interferon-
alpha-2b,
anticoagulation,
heparin, and surgery
Heyd et al. 10 Primary and adjuvant LC in 80% at F/U. Median F/U 42
(2011) RT dose 30–45 Gy Progression occurred months.
beyond target volume 40% had G1 side
effects
Dunbar et al. 4 3—radiation therapy 3—alive with no evidence Authors
(1993) (32.5–45 Gy). of disease. recommend
1—surgery 1—dead with progressive 40–45 Gy in 2 Gy
disease despite fractions.
surgery + radiation A good review of
therapy the literature and
discussion of the
disease process
(continued)
Freedy and 1 Biopsy Not discussed A discussion of
Bell (1992) 31-year male, radiographic
temporomandibular findings, but not of
joint management
Kulen 1 Biopsy, radiotherapy Decrease in pain, Had 2 normal
Kampff et al. 23-year female, 40 Gy in 2 Gy fractions radiographic improvement pregnancies and
(1990) pelvic bones deliveries despite
massive pelvic
osteolysis
Dickson 44-year woman, left Biopsy, excision with No radiologic Discussion of
et al. (1990) forearm bone graft, progression, restoration of pathologic findings
radiotherapy, 25 Gy in function
12 fractions. Fusion of
arm
Handl-Zeller 16 years, pelvis Biopsy, radiation Pain relief, recalcification
and 30.6 Gy in 180 cGy on radiographs
Hohenberg fractions
(1990)
Turra et al. 1 Resection with graft, At 5 months, Authors conclude
(1990) 19-year male, autogenous fibular incorporation of fibula. that autogenous
humerus transplant At 20-year follow-up, bone grafting may
clinically stable be an alternative to
radiotherapy
Mendez 1 Open reduction with No effect of Diagnosis confused
et al. (1989) 12-year girl, femur fixation, chemotherapy chemotherapy with hemangioma
with platinum and initially
actinomycin D,
disarticulation
Choma et al. 1 Widespread disease. Dead of systemic disease Review of the
(1987) 23-year male, Received palliative and pulmonary literature
scapula radiotherapy to hemorrhage
multiple sites
2.5–7.5 Gy
Carneiro and 1 Excision and Lysis of grafts,
Steglich 13-year girl, hand grafting—radiotherapy progression. Stabilization
(1987) 2400 rads/21 days after radiotherapy with
return of function
Listewnik 1 Radiotherapy, 20 Gy Resolution
et al. (1986) 16-year-old boy, ribs 7–10 fx ribs,
radiotherapy to third
rib
Hanly et al. 1 Biopsy, radiotherapy Reduction in pain,
(1985) 62-year female, hand 3000 rad in 15 improvement in function,
fractions via cobalt 5 1/2-year follow-up, she
had new bone formation
Bek et al. 2 Attempted Arrest of osteolysis and
(1981) unsuccessful resection; recovery for 8 months and
followed by 9 years
radiotherapy, 40 Gy/4
weeks
10 Giant Cell Tumor ing, and high local recurrence rate, particularly in
(Osteoclastoma) the sacrum and spine. Giant cell tumor is not a
radioresistant tumor as once believed, as 40–60 Gy
Although giant cell tumor is termed a benign is often used. Complications following modern
tumor, occasionally these “benign” tumors metas- radiotherapy are minor, and local control rates are
tasize, most commonly to the lungs. It is charac- in the range of 60–100% in the more recent series.
terized by the presence of multinucleated Specifically, osteoclasts from giant cell tumor of
osteoclast-like giant cells (NCI Thesaurus Code: the bone express the receptor activator of nuclear
C3055). The primary treatment for giant cell factor kappa-B (RANK), which renders this dis-
tumor is surgical. Wide resection has better tumor ease potentially responsive to the RANK ligand
control than intralesional curettage. Local recur- inhibitor, denosumab. Denosumab may be used in
rence rate is high after curettage. These tumors the neoadjuvant setting to facilitate surgery or in
are often located in sites where resection is diffi- the definitive setting for unresectable disease
cult or causes neurologic dysfunction and spinal (Lipplaa et al. 2019). Thus, the addition of deno-
instability. Radiation therapy is often used because sumab to the available treatment options may alter
of major bone destruction, which can be devastat- the future role of radiotherapy.
Steen et al. (2020) 8 Adjuvant EBRT 48 Gy/26 fractions Median DASH score 8.1 (0–28). Median time since RT 5.4 years
Most common side effect was nail changes
(discoloration)
Ouyang et al. 37 Adjuvant CRT 40–50 Gy in 20–25 Local control rates for CRT and IMRT were 60%
(2017) fractions and radical IMRT and 58%, respectively. Use of RT and RT dose was
60–65 Gy in 22–25 fractions not a risk factor for local recurrence.
40.5% (n = 15) developed local recurrence with
median disease-free survival of 93.5 months (3–214)

Yin et al. (2015) 4 Adjuvant RT 4–6 weeks post-op, 50% had local recurrence and distant metastasis and Mean F/U 41 months (3–75)
30–50 Gy had passed at F/U
van der Heijden 5 Curettage and EBRT (50–64 Gy) 60% (n = 3) dead of disease, 40% (n = 20) alive with Median F/U 98 months (6–229)
et al. (2014) disease
Ming et al. (2013) 6 Adjuvant RT median dose 51 Gy RFS rates at 3 and 5 years were 89.1% and 75.5%, Median F/U 86.5 months
(40–60 Gy) respectively. No significant effect of RT vs. no RT (15–193)
Shi et al. (2013) 34 Definitive RT (n = 21) and adjuvant No data comparing RT vs. surgery + RT. Median F/U 16.8 years
RT (n = 13), mean 45 Gy (35–55) in Overall, 5-, 10-, and 15-year OS rates were 97%, (1.4–33.7)
1.2–2.33 Gy/fraction. Mixture of 93%, and 81%, and local control rates were 85%, No secondary RT-related
Co60, 6–20 MV photon and 81%, and 81%, respectively malignancies
electrons
Coroneos et al. 10 35 Gy/14 or 48 Gy/24 No recurrence at median F/U (3.1 years) Median F/U 3.1 years.
(2012) No long-term complications.
Hand function not adversely
affected
Kriz et al. (2012) 35 Co60 gamma rays or 5–15 MV Total RT dose >42 Gy (vs. <42 Gy) improved local Median F/U 65 months.
photons with median dose 42 Gy control at 6 months (p = 0.04). No >G3 toxicity and no
(35–60) in 1–3 Gy fractions 5-year overall survival, disease-free survival, local RT-related secondary
control, and distant metastasis-free survival rates malignancies
were 90%, 59%, 60%, and 89%
Klenke et al. (2011) 4 Unspecified adjuvant EBRT No RT-specific outcomes Mean F/U 108.4 months
(36–233)
Roeder et al. (2010) 5 IMRT median dose 64 Gy (57.6–66) 100% OS, 80% LC—1 patient had local disease Median F/U 46 months
with conventional fractionation progression 3 months post-RT, required extensive (30–107).
surgical salvage No severe or late toxicities of RT
Ruggieri et al. 21 Pre-op 47.5 Gy (n = 1) and post-op Local recurrence at F/U 91% (RT) vs. 89% (no RT). Median F/U 108 months
(2010) (n = 20), 36–56 Gy No significant effect of RT (36–276)
(continued)
141
142
Ruka et al. (2010) 77 Definitive RT median dose 56 Gy 5- and 10-year PFS rates were 83% and 73%, Median F/U 58 months.
(26–89), in 1.8–2 Gy/fractions respectively No acute or late RT-related
LC 84% (n = 65) at F/U. Progression in 12 patients complications
within radiation field, of which 9 successfully treated
with salvage surgery
Thangaraj et al. 2 Embolization with RT (1 for initial 1 with no evidence of disease, 1 alive but continues F/U 2–21 years
(2010) disease and 1 for recurrence), 45 Gy to be incontinent with back pain
in 25 fractions
Balke et al. (2009) 3 Adjuvant EBRT (n = 2 of 50 Gy over EBRT patients have no evidence of disease. Proton Median F/U 3 years (1–11)
3 months; definitive RT (n = 1) with patient has stable disease
protons (no dose or fractionation)
Chekrine et al. 2 EBRT of 40 and 45 Gy Both patients alive without progression at 18 months
(2009) and 5 years
Junming et al. 18 Adjuvant EBRT 4–6 weeks post-op, Subtotal resection (n = 6): 4 local recurrence, 1 lung Mean F/U 67.8 months (36–124)
(2008) 30–50 Gy in 20 fractions met. At F/U, 2 had no evidence of disease, 1 alive
with disease, and 3 dead.
Total spondylectomy + RT (n = 12): 100% with no
evidence of disease
Noel et al. (2006) 2 Combined 3DCRT proton and 1 patient relapsed 4 months post-RT and the second F/U 8 and 83 months
photon RT 59.4 and 65.2 Gy, had no evidence of disease
respectively, in 1.8–2 Gy fractions
Leggon et al. 11 EBRT 40–60 Gy as adjuvant RT No significant impact of RT vs. surgery + RT on Median F/U 95.8 months
(2004) (n = 2), with chemotherapy (n = 2) local control. Larger doses of RT (<45, 45–55, or (11–254).
and definitive treatment (7) >55 Gy) had no impact on local recurrence. RT-induced sarcoma developed
Recurrence rates were 49% (RT only) and 46% in 11% of patients
(adjuvant RT)
Caudell et al. 25 EBRT median dose 46 Gy (25–65) 5-year overall survival, disease-free survival, local Median F/U 8.8 years (0.67–34)
(2003) control, and distant metastasis-free survival rates
were 91%, 58%, 62%, and 81%.
Recurrent disease (n = 12) had a trend toward lower
disease-free survival (83% vs. 33%, p = 0.06)
Feigenberg et al. 24 MV EBRT median dose 43 Gy Local control rates using <40 Gy vs. >40 Gy were Mean F/U 12 years (2.4–25.8)
(2003) (35–55) in 1.67–2.33 Gy/fraction 86% and 67%, respectively (p = 0.03 when study
data combined with others for meta-analysis).
Overall local control 77% (81% for primary disease,
70% for recurrent disease)
Feigenberg et al. 3 EBRT 16 Gy/10 to whole lung with 67% (n = 2) survived 7.5 and 13 years with complete
(2002) 35–45 Gy boost to other sites of resolution of detectable disease (1 required
gross disease additional RT to metastasis). 1 passed away from
progression of lung metastasis
Hug et al. (2002) 4 Adjuvant combined 3DCRT proton 100% of patients alive with stable disease Mean F/U 4.4 months (3.1–5.8).
(22) and photon therapy, mean dose 1 patient developed RT-related
59 Gy (57.6–61.2) in 1.8 Gy/fraction partial pituitary insufficiency
Malone et al. 21 35 Gy/15 (most common) Local control in 90.5% (19/21); 2 failures were Mean F/U 15.4 years.
(1995) salvaged for total control rate of 100% No serious late toxicities,
malignant transformation, or
radiation-induced cancer
Turcotte et al. 26 (16 initial 5—biopsy only 4/5 treated with radiation only were cured Radiation doses ranged from 30
(1993) therapy, 10 21—resection to 60 Gy. Follow-up 1–14 years.
recurrent). All 21 (81%) received radiation Local recurrence rate 25%, 3
with sacral Average dose 48 Gy patients had malignant
tumors 5 received radiation only transformation, 3 “benign”
tumors metastasized to lungs
Bennett et al. 16 Surgical curettage followed by 12/16 (75%) tumors were controlled locally. Surgical Doses of 35–54 Gy (mean
(1993) radiotherapy salvage was successful in all 4 failures 42.75 Gy) megavoltage, 63% of
patients were followed for 5
years.
No secondary sarcomas occurred
Sanjay et al. (1993) 24; all with spine Surgery, all 24 one-stage or 5/14 cases treated by one-stage surgery recurred; Authors recommend that
tumors two-stage radiation for recurrent 5/10 cases treated by two-stage surgery recurred; 1 radiation be reserved for
lesions of 7 patients irradiated, developed a sarcoma incompletely resected lesions of
those with local recurrences
because of the approximately
10% risk of sarcomatous
transformation
Bertoni et al. 11—site: skull Intralesional excision in 11. 10 6 patients survived for 4–34 years Authors recommend surgical
(1992) (sphenoid bone patients had postoperative radiation ablation and postoperative
and surrounding therapy radiation therapy
area)
Hefti et al. (1992) 1—site: tibia Intralesional resection and bone 6 years after resection, the patient developed Radiation therapy was not
grafts malignant transformation administered
Tubbs et al. (1992) 475 patients, 13 Excision—10 All 13 developed pulmonary metastases. 7/13 (54%) Not all patients developing local
of whom Curettage and XRT—3 had local recurrence before developing metastatic recurrence and/or pulmonary
developed disease metastases received irradiation
metastases
143
(continued)
144
DeGroof et al. 1 site = L1 Surgery × 3, followed by radiation Recalcification occurred. At 15-year follow-up, the Authors recommended a
(1990) 4000 rads patient is stable combined surgical and
radiotherapeutic approach using
low doses of radiation
Zhu and Steiner 1 site—femur Curettage 6 months after resection, lesion recurred locally 22 Malignant transformation
(1990) months later, lesion recurred again, with malignant following surgery
transformation
Schwartz et al. 13 patients Radiation 42–68 Gy 11/13 (85%) controlled locally. Mean follow-up—6.5 years. No
(1989) 7—primary Rx Salvage surgery successful in the others long-term complications of
4 recurrence, 3 radiation therapy
metastases Authors conclude that radiation
is a good treatment for the
medically inoperable and a good
alternative to complex and
difficult surgery
Daugaard et al. 10 patients Radiation 23–75 Gy 3/10 cases recurred after 2–21 months. All had Mean follow-up—7.6 years
(1987) 8—primary received radiation doses of 23–30 Gy
2—recurred
Seider et al. (1986) 15 patents, 10 Radiation in 10, 36–66 Gy. Surgery 7/10 patients free of recurrence 48–360 months, No radiation-induced
with follow-up in 8, chemotherapy in 3 mean—192 months. 3 cases metastasized sarcomatous transformation
information
Chen et al. (1986) 35 10—surgery and radiation All 10 survive.
25—radiation alone 14/17 (82%) controlled locally—doses >35 Gy,
11/13 (85%) controlled locally—doses >40 Gy
Rock et al. (1986) 26 18—radiation, details of doses All 26 patients had malignant giant cell tumor of Rx 4–39 years earlier.
unclear bone at a site of a previous benign giant cell tumor. Fibrosarcoma occurred 3 × as
All 26 had previous attempt at local control frequently as osteosarcoma
Dahlin (1985) 407 Details not provided In 28 cases, malignant change developed, of which A retrospective review of Mayo
21 had received radiation therapy. Clinic Experience
8 cases developed metastases
Duncan et al. 30 3—radiation 52% of the 19 appendicular lesions treated by
(1983) 19—curettage curettage recurred.
4—local excision (appendicular Salvage therapy successful in 89%.
lesions) 6.7% developed pulmonary metastases
4—partial excision followed by
radiation (axial lesions)
Bell et al. (1983) 15 Supervoltage radiation 32.5 Gy/18 fx All are disease free Follow-up of 2–21 years, mean
to 55 Gy/20 fx 12 years. No cases of malignant
transformation
Harwood et al. 9 Co60 8/9 controlled. Authors recommend
(1977) 3500/15 fx–5500/25 fx 1—geographic miss and surgically salvaged 3500 rads/15 fx/3 weeks.
Recalcification may be slow
Larsson et al. Radiotherapy only (2) Follow-up of 6–16 years. No recurrences All were cases of giant cell
(1975a, b) Surgery plus radiotherapy (1) tumors of the spine. Authors
Surgery only (2) emphasize that radiotherapy
Details of radiotherapy: total dose of should not be used for tumors in
3100–5000r other regions, but that it seems
justified for tumors of the spine
Larsson et al. 43 Primary treatment: 1. 5/8 (62%) remissions Giant cell tumor of bone. There
(1975a, b) 1. Curettage alone 2. 9/12 (75%) remissions were six deaths (11.3%) due to a
2. Curettage plus grafting 3. 4/10 (40%) remissions malignant course of the tumor.
3. Radiotherapy alone 4. 2/4 (50%) remissions The patient had received
4. Radiotherapy plus curettage 5. 1/7 (14%) remissions radiotherapy
5. Resection 6. 1/2 (50%) remissions
6. Amputation
DePalma et al. 10 Complete en bloc excision followed Follow-up of 2–12 years. No recurrences All were cases of giant cell
(1974) by fusion of joint or bone grafting tumor of bone. 8/10 were located
in the femur
Martins and Dean 1 Radiotherapy: Patient became asymptomatic for 2.5 years. From Case of giant cell tumor of the
(1974) 5000r/40 days, Co60 that time on, the patient experienced progressive sphenoid bone
6.5 × 6.5 cm opposing cellar ports deterioration and finally death due to a poorly
differentiated spindle cell sarcoma of the sphenoid
sinus
Marcove et al. 25 Curettage followed by cryosurgery 2/25 obvious clinical recurrence. Five of these eight tumors were
(1973) 6/25 residual foci as demonstrated by “second-look” controlled with repeat
biopsy procedure cryotherapy
(continued)
145
146
McGrath (1972) 52 Primary treatment: Recurrences: Giant cell tumor of bone. There
1. Curettage plus graft (20) 1. 9/20 (45%) was no relationship between the
2. Curettage plus radiotherapy (5) 2. 1/5 (20%) malignant change of previously typical dose and course of radiotherapy
3. Curettage plus graft plus tumor and the incidence of typical or
radiotherapy (2) 3. 1/2 (50%) malignant recurrences
4. Local excision (1) 4. 0/1 (0%)
5. Local excision plus radiotherapy 5. 0/1 (0%)
(1) 6. 0/7 (0%)
6. Resection (7) 7. 0/1 (0%)
7. Resection plus radiotherapy (1) 8. 6/12 (50%) malignant change in four
8. Radiotherapy alone (12) 9. 0/3 (0%)
9. Amputation (3)
Radiotherapy dose: 3000–9500r/l–3
courses/up to 18 months
Shifrin (1972) 24 Includes both primary and secondary Recurrences: All were cases of giant cell
treatment. 1. 4/10 tumor of bone. Subsequent
1. Curettage (10) 2. 0/7 developments: Metastasis (1)
2. Resection (5) or amputation (2) 3. 2/7 Osteogenic sarcoma (1)
3. Radiotherapy (7) Fibrosarcoma (1)
Both sarcoma patients had been
treated by irradiation
Osteonecrosis and pathologic
fracture (1)
Emley (1971) 14 1. Biopsy plus irradiation (6) Includes 13 previously reported cases plus the case Review of the literature of
2. Excision only (3) reported by the author: reported cases of giant cell
3. Excision and irradiation (5) 1. 4/6 favorable results (cured or improved) tumors of the sphenoid bone
2. 1/3 favorable results
3. 1/5 favorable results
Dahlin et al. (1970) 195 Without radiation: Minimum follow-up 3 years: All were giant cell tumors of
1. Curettage plus cautery and/or Recurrences: bone. Seventy-seven percent
bone graft in some cases (41) 1. 16 /41( 39% ) ïü were located at or near the end of
2. Excision (6) ý 42.6% a major tubular bone of the
3. En bloc resection (11) 2. 4 /6 ( 67% ) þï extremities
4. Amputation (10) 3. 0 /10 Seventeen patients (8.7%) had
With radiation: Amputation for nonunion was subsequently malignant giant cell tumors. In two
5. Curettage plus cautery and/or performed in one patient patients, the sarcomas were found
bone graft in some cases (23) in recurrent tumors. These patients
4. 0/10
6. Excision (13) had not been treated by irradiation

7. Radiation alone (7) 5. 11/23 ( 48% ) ïü at any time. In 11 patients, the
ý 47.2% sarcomas developed at an interval
6. 6/13 ( 46% ) ïþ
of 3.7–38 years after therapy that
7. 4/7 dead or diseases within 2 years included irradiation administered
2/7 subsequently required amputation before supervoltage equipment
1/7 clinically well at 2 years was available
Goldenberg et al. 218 1. Curettage (45) Recurrences and complications: All were cases of giant cell
(1970) 2. Curettage plus graft (91) 1. 37/45 (82%) tumor of bone. Complications
3. Resection (44) 2. 55/91 (60%) include recurrences or seeding,
4. Resection plus graft (22) 3. 28/44 (64%) metastases, nonunion of graft,
5. Amputation (10) 4. 17/22 (77%) fracture of graft, infection, foot
6. Irradiation (10) 5. 0/10 (0%) drop, irradiation sarcoma, and
Radiotherapy: 6. 7/10 (70%) death
Radium application. Radon seeds, Radiotherapy was used in conjunction with other These cases were compiled from
roentgen therapy, or Co60 therapies in 46 cases a variety of sources. Five had
Dose range: 1120–5320r Results: been previously reported. The
8/46 healing without complications and minimum patients with postirradiation
follow-up of 3 years sarcoma died 9–31 years after
29/46 recurrence, metastases, or death diagnosis
Johnson and Riley 24 Initial treatment: Recurrences: All were cases of giant cell
(1969) 1. Curettage (16) 1. 8/12, four lost to follow-up tumor of bone. Both patients in
2. Irradiation (3) 2. 2/2, one lost to follow-up this series who died with
3. Local resection (3) or amputation 3. 0/2, three lost to follow-up malignant giant cell tumor had
(2) received irradiation at a time
when the tumor was
histologically benign in one case
and clinically benign in the other
case
(continued)
147
148
Friedman and 11 treated, 46 Radiotherapy: Recurrences: All were giant cell tumors of
Pearlman (1968) from literature GÇT of the jaw (13): GCT of jaw: 0/13 bone. Eleven cases treated by the
1850r/22 days to 3000r/60 days GCT of the long bones: 9/20 author, 46 from the literature
GCT of the long bones (20): GCT of membranous bones: 2/13
2000r/21 days to 6264r/33 days GCT of spinal column: 4/12
(doses smaller than 3000r/21 days Death from radiation myelitis occurred in one
were unsuccessful) patient who received 6000r/120 days
GCT of membranous bones (13):
2300r/34 days to 5700r/6 months (2
courses)
GCT of spinal column (12):
980r/17 days to 6000r/120 days
(successful tumor dose ranged from
2200r/21 days to 5100r/34 days)
Riley et al. (1967) 2 Case #1: Case #1: Soft tissue recurrence of GCT of
Radiotherapy to GCT of left Submucosal nodules removed from the vaginal wall bone after irradiation and
innominate bone followed by total at the site of previous resection at 7 months, 17 excision
excision (which necessitated months, and 32 months post-op. They were benign
resection of part of the vaginal wall) giant cell tumors similar histologically to the
Case #2: previously resected lesion
Excision followed by radiotherapy Case #2:
2125r/13F/2 weeks to head of ninth First recurrence treated by excision and radiotherapy.
rib. Recurrence was treated by Tumor involving the eighth and ninth thoracic
excision and radiotherapy 4000r vertebrae was found 2 years after treatment for
recurrence. There was also a nodule in the scar of the
old incision, which proved to be malignant
GCT. Patient died 15 months later from extensive
disseminated tumor
Berman (1964) 5 Radiotherapy: 2/5 alive and well for 4–12 years All were giant cell tumors of the
2500r/40 days to 5100r/34 days. One 1/5 alive for 17 years with total disability vertebrae
patient received 600r in two courses 2/5 dead, one with malignant transformation, one
over a period of approximately 6 with complications due to the natural progression of
months the disease
Mnaymneh et al. 67 Primary: Recurrences: Giant cell tumor of bone. Of the
(1964) 1. Curettage (31) 1. 13/23, primary recurrence nine tumors treated by radiation
2. Curettage plus irradiation (4) 6/8, second recurrence alone or radiation combined with
3. Radiation (6) One with malignant change curettage or partial excision,
4. Partial excision and post-op 2. 4/4, one recurred as a fibrosarcoma eight recurred. Malignant
radiotherapy (3) 3. 2/3, primary recurrences transformation in 4/67, who had
5. Partial excision only (2) 3/3, secondary recurrences received radiation therapy
6. Total excision (21) 4. 2/2, primary recurrences
1/1, secondary recurrences
5. One half tumor progressed as a fibrosarcoma
6. No recurrence
149
11 Hemophiliac Arthropathy joints of hemophiliacs. Radioactive colloids and

even external radiation have been used to improve
Intra-articular hemorrhage, joint swelling, prolif- the future of patients having this malady.
erative synovitis, and reduced range of motion are
sequelae of repeated hemorrhagic episodes in the
Total # of
patients,
Author, year age Treatment Results Notes
Kong et al. 37 EBRT median 9 Gy For those with >3 bleeds/month, Median F/U 87 months.
(2010) (9–30) in 1.5–3 Gy significant decrease in bleeding No RT-induced secondary
fractions episodes: pre-RT 5.0 vs. 2.7 at 1 malignancies
year and maintained at 1.3–2.0 at
10 years (p = 0.018)
Erken (1991) 35 2–5 mCi 2–12-year follow-up, 47 joints pain Hemorrhage was
Ages 90
Yttrium silicate free, 13 joints no further decreased from 4/month
5–20 100–200 nm in size hemorrhage to 2/year.
years 47/58 joints improved.
Immobilization is needed
to prevent joint leakage of
isotope
Fernandez- 43 198Au, 185Re, 30 cases without recurrence (60%)
Palazzi et al. Ages 99Tc 14 cases with reduced recurrence
(1984) 6–43 (28%)
years 88% joint improvement and
positive result
Hilgartner 1 750 rad, 125 rad/ 5 years, still doing well
and Arnold Age 2 day plus
(1975) years cryoprecipitate
12 Heterotopic Bone Formation most proximal aspect of articulating joints for

functional healing (shielding to avoid nonunion)
Heterotopic ossification is the abnormal develop- and theoretical long-term risks of radiation
ment of bony structures in what are normally soft dependent on age, location of treatment, and por-
tissues. The condition can be caused by surgeries, tal and reproductive status. The use of preopera-
fractures, or traumas. The presence of abnormal tive single-fraction irradiation has the advantage
bone leads to limitations in the affected joint’s of convenience and ease of transportation of an
range of motion (Unified Medical Language often relatively immobile patient. Preoperative
System—Concept Unique Identifier C0029396). radiation is as effective in randomized trials.
Radiation therapy to prevent the sequelae of Postoperative radiation ensures that only patients
pain, limitation of motion, and reoperation are who had undergone surgery will receive radia-
used in high-risk patients. Originally, the dose of tion, thus avoiding unnecessary radiation if sur-
20 Gy (known to inhibit bone growth in children gery is cancelled or delayed beyond 5 days. A
with cancer) was employed, most effectively 700 cGy single dose is effective in the preopera-
beginning within 3–4 days of surgery. As experi- tive or postoperative setting. A commonly used
ence has been gained, both preoperative and post- measure of outcome is the Brooker classification
operative irradiation not greater than 5 days after (Brooker et al. 1973), which divides the extent of
surgery has been used in doses varying from a the ossification at the hip into four classes based
single fraction of 4 Gy to fractionated 10 and on radiological findings on plain anterior-
20 Gy. Pertinent issues include shielding the posterior pelvic radiographs.
Author, year Sex/age Treatment Results Notes
Cichos et al. (2020) 104 Adjuvant RT 7 or 8 Gy/1 within 72 h No difference in HO development Median F/U 13 months
post-op, for prophylaxis Significant increase in (0.5–77)
noninfectious wound
complications of 20.2% (adjuvant
RT, n = 104) vs. 6.6%
(indomethacin n = 167, p = 0.002)
vs. control (5% n = 202,
p < 0.0001)
Freibott et al. (2020) 6 Contracture release + adjuvant EBRT Significant pre- and post-op Mean F/U 1.6 years
7 Gy/1 within 48 h post-op difference in elbow arc motion— (0.09–8.53)
flexion, extension, pronation,
supination (p < 0.01)
Honore et al. (2020) 19 Perioperative RT 7 Gy/1 day before No significant effect of RT on HO Median F/U 11.7 months
surgery recurrence, but was associated (IQR 5.2–29.8)
with sepsis requiring surgical
revision (OR 4.70, 95% CI
1.38–16.26, p < 0.05)
Lee et al. (2020) 9 Hypofractionated RT of 14 Gy/2, 9 Gy/1, 89% had reduction of HO with Median F/U 7.1 months
12 Gy/2, 18 Gy/3, 16 Gy/2, or 21 Gy/3 56% (n = 5) >50% reduction at (5.1–23.1)
F/U No adverse RT-related
effects
Pakos et al. (2020) 50 Adjuvant THA RT 7 Gy/1 within 3 days No effect of RT on the rate of F/U 10 years
post-op with indomethacin vs. THA implant loosening or
indomethacin alone on the rate of THA RT-related tumors
implant loosening
Davis et al. (2019) 35 Case-control study of preoperative 6 MV HO development was 35% (RT,
EBRT 7.5 Gy/1 for prophylaxis n = 17) vs. 83% (no RT, n = 18),
p = 0.015. RT also associated with
significantly smaller HO size as
well (282.7 mm vs. 1221.5 mm,
p = 0.026)
Hess et al. (2019) 25 11 pre-op and 14 post-op, receiving 7 Gy/1 Preoperative RT associated with Median F/U 34.6 months
earlier radiographic development (4.4–143)
of HO (median 4.0 vs. 15.7
months, p = 0.03). No difference
in symptomatic HO
Morcos et al. (2018) 9 Postoperative RT 6–12 weeks post-op, 89% demonstrated no further Min 2-year F/U
7 Gy/1 to HO developing after THA progression of HO
151
(continued)
152
Ruo Redda et al. (2018) 31 Pre-op (n = 25) and post-op (n = 6) RT: Overall, 74% had complete Median F/U 67 months
7 Gy/1, 8 Gy/1, 12 Gy/3, 15 Gy/5 responses, 22.6% had partial No RT-related adverse
response, and 6.5% had HO effects
relapse at same site 19 and 12
months after treatment
Tao et al. (2018) 20 (15 and 5 with and without Most common 8 Gy or 7 Gy in 1 fraction, Radiographical HO progression
preexisting disease, respectively) for prophylaxis 60% (no preexisting disease) vs.
6.7% (existing disease), p = 0.032
Liu et al. (2017) 147 Randomized double-blind comparing Significant difference in HO Minimum 6-month F/U
4 Gy/1 vs. 7 Gy/1 following THA (1–2 progression: 25% (7 Gy) vs.
days post-op) for prophylaxis 42.3% (4 Gy), p = 0.026
No significant difference in
Brooker classification
Macheras et al. (2017) 26 Preoperative indomethacin and RT 7 Gy/1 No severe HO recurrence, or Mean F/U 31.4 months
RT-related complications (24–40)
Museler et al. (2017) 244 EBRT 7 Gy/1 mean 4.9 days after HO 5.3% (n = 13) experienced HO Mean F/U 63.2 days
diagnosis relapse (8–295)
No RT-related adverse
effects, other than 1
patient who suffered
joint ankylosis requiring
surgical resection
Citak et al. (2016) 13 EBRT 7 Gy/1 using 6 or 15 MV photons No HO recurrence at F/U and Mean F/U 88.8 days
improved shoulder ROM (30–198)
No RT-related adverse
effects
Davis et al. (2016) 24 Postoperative RT 7 Gy/1 within 72 h Adjuvant RT decreased the risk of Mean F/U 37 weeks
post-gluteus minimus debridement for clinically important (Brooker III– (11–149)
prophylaxis IV) HO (4% vs. 32%, p = 0.02)
and did not significantly increase
the length of hospital stay
Lee et al. (2016) 3 EBRT 20 Gy/2 Decreased pain and increased F/U 4–6 months
ROM immediately after RT that
persisted to 4 and 6 months
post-RT
Boffeli et al. (2015) 11 7 Gy/1 either 24 h pre-op or within 72 h 82% had no signs of HO; 18% had F/U 6 weeks
post-op for prophylaxis low-grade HO not clinically
relevant
Rashid et al. (2015) 39 (28 elbow fracture, 11 Postoperative EBRT 7 Gy/1 24 h within No significant effect of RT on the Minimum F/U 12
acetabular fracture) surgery for prophylaxis development of HO, wound months (13–25)
infection, or nonunion for elbow
or acetabular fractures
Overall, 15% (n = 6) of patients
receiving RT had wound infection,
but not significant
Weng et al. (2015) 53 Adjuvant RT 5 Gy/1 vs. control (no No significant difference in HO F/U min 12 months
post-op RT), for prophylaxis formation
Archdeacon et al. (2014) 146 50 pre-op and 96 post-op RT 6–10 MV No difference in HO frequency F/U 6–97 months
photons of 7–8 Gy/1 between pre-op and post-op
groups (p = 0.6)
Burnet et al. (2014) 34 Post-op 8 Gy/1 for prophylaxis 82% had no development of HO Mean F/U 110 weeks
and 18% had Brooker Class I (13–534)
Mourad et al. (2013a, b) 257 Adjuvant EBRT 6–18 MV 7 Gy/1 APPA HO development was 29% Median F/U 6.6 years
within 72 h of surgery for (nonpregnant adjuvant RT; OR (1–12)
prophylaxis ± indomethacin (nonpregnant, 0.4) vs. 6% (pregnant with no
n = 257) vs. surgery only (n = 16) prophylaxis; OR 0.06)
Mourad et al. (2013a, b) 532 Adjuvant RT 7 Gy/1 within 72 h post-op Overall HO incidence 21.6, with Median F/U 8 years
for prophylaxis significantly decreased rates with
CT-based RT (6.6%) vs. clinical
setup (24.6%); p < 0.001
Kruser et al. (2012) 24 Adjuvant SRA RT 7.5 Gy/1 within 72 h 1 case of clinically significant HO F/U min 1 year
post-op for prophylaxis ± NSAID vs. in each of treatment and control
control No significance of RT
Mourad et al. (2012a, b, 419 Post-op EBRT 7 Gy/1 within 72 h after HO development in 18% (BMI
c) surgery for prophylaxis <40) vs. 47% (BMI >40);
p < 0.001
Mourad et al. (2012a, b, 395 Post-op EBRT 7 Gy/1 within 72 h after Significant positive correlation
c) surgery with increasing BMI and incidence
of HO, p < 0.0001
Mourad et al. (2012a, b, 585 Adjuvant RT 7 Gy/1 within 72 h post-op Overall development of HO: 18%. F/U at 2 weeks, 1, 3, 6,
c) for prophylaxis Correlation between risk of HO and 12 months
and length of time to RT
(p < 0.0001)
(continued)
153
154
Le Duff et al. (2011) 885 Preoperative with indomethacin and Decreased HO incidence when RT Min F/U 2 years
7 Gy/1, with varying wound irrigation and added to control arm for those
use of a surgical plastic drape to collect with B/L surgery (p = 0.048) and
bone debris when plastic drape is used
(p = 0.029)
Hashem et al. (2011) 44 Adjuvant RT 7 Gy/1 with 6 or 18 MV Only 2% (n = 1) developed Min F/U 1 year
photons within 72 h post-op heterotopic bone formation No RT-related toxicities
Mishra et al. (2011) 30 Adjuvant RT 7 Gy/1 24–48 h post-op for 10.5% developed recurrent HO in Median F/U 16 months
prophylaxis upper extremity while none for RT (2–143)
to knee 1 patient each with
post-op wound infection,
ruptured triceps tendon,
and fracture within RT
field
Strauss et al. (2011) 52 Adjuvant RT 5–7 Gy/1 with 6 MV photons 48% had radiographical HO that Median F/U 136 days
within 24 h post-op for prophylaxis was not functionally significant No RT-related
complications
Jensen et al. (2010) 12 Post-arthrotomy RT 10 Gy/5 1–3 days No symptomatic reformation of Median F/U 16.4 years
post-op for prophylaxis HO in 71% and 48% of patients at (2.5–19.2)
5 and 10 years No >G1 RT-related
toxicities
Maender et al. (2010) 9 7 Gy/1 either 24 h pre- or post-op for 11% (n = 1) developed HO Mean F/U 5 years (3
prophylaxis months–14 years)
Hamid et al. (2010) 21 Randomized to 7 Gy/1 within 72 h post-op Study terminated early due to Clinical and radiographic
for prophylaxis vs. observation (control) adverse events. Nonunion was F/U at 6 weeks and 3 and
38% (treatment arm) vs. 4% 6 months post-op
(control), p = 0.007
Robinson et al. (2010) 36 Adjuvant 6 Gy/1 (n = 2) or 7 Gy/1 (n = 24) 8% developed new HO after RT, Median F/U 8.7 months
within median 1 day post-op (1–4 days) although no functional
compromise. All patients had
improvement in range of motion
Pakos et al. (2010) 71 Adjuvant 7 Gy/1 or 10 Gy/5 within 3 days 7% had radiographic incidence of Median F/U 12 months
post-op for prophylaxis, with concurrent HO only (no clinical significance),
indomethacin with significant benefit for patients
with bilateral B/L THA. No
statistical difference between RT
dose fractionations
Cipriano et al. (2009) 30 each in treatment and control Adjuvant RT 7 Gy/1 within 4 days post-op Higher incidence of HO in Median F/U 12.7 months
for prophylaxis treatment group (15%) vs. control (6–33)
(5.1%), with no significant
difference in intraoperative ROM
or delayed wound healing
Heyd et al. (2009) 20 Perioperative RT 7 Gy/1 for prophylaxis 90% had no progression of HO Mean F/U 43.3 months
with 65% having no functional No adverse RT-related
impairments effects
Nasr et al. (2009) 14 Adjuvant RT 7 Gy/1 with 18 MV photons Radiological evaluation (Brooker No acute adverse event.
within 4 days post-op. 9 patients within 1 score) 6 months after RT: No HO All patients derived
day of surgery. Parallel opposed technique, development in 85.7% and 57.1% clinical benefits
for prophylaxis of patients receiving RT for irrespective of radiological
primary and secondary response
prophylaxis, respectively
Pakos et al. (2009a, b) 44 Postoperative indomethacin and RT 7 Gy/1 At 6 months post-op, no F/U 6 months post-op
for prophylaxis significant difference of adding No RT-related adverse
post-op RT on the incidence of HO effects
(27.3 RT vs. 34.5% no RT, p = 0.5)
Pakos et al. (2009a, b) 96 Adjuvant RT 7 Gy/1 within 15 days HO incidence 4% (RT + F/U 6 months
post-op with indomethacin vs. indomethacin, total n = 96) vs.
indomethacin alone 26% (indomethacin only, historical
control n = 50), p < 0.05
Shapeero et al. (2009) 25 EBRT (n = 17), EBRT + brachy (n = 7), Compared to resection alone, Median F/U 3.75 years
extracorporeal radiation, and patients who received RT in (malignant) and 2.79
reimplantation (n = 1) addition to resection had lower (benign)
rates of inflammatory No p-values reported
pseudotumors (0 vs. 11.5%), acute
muscle atrophy (0 vs. 7.7%),
heterotopic ossification (0 vs.
11.5%), and nerve transection (0
vs. 7.7%)
However, patients who received
RT had higher rates of seromas (76
vs. 7.7%), edema (92 vs. 19.2%),
muscle inflammation (80 vs.
19.2%), chronic muscle atrophy
(48 vs. 7.7%), osteoporosis (28 vs.
19%), fractures (28 vs. 0%), bone
infarct (4% vs. 0%), and nerve
155
entrapment (20 vs. 3.8%)

(continued)
156
Balboni et al. (2007) 84 Adjuvant THA RT 750cGy/1 for HO progression in 20% Median F/U 24 months
prophylaxis with and without shielding of (unshielded) vs. 48% (shielded),
THA components p = 0.009. Multivariate analysis
showed shielding to be a
significant predictor for RT failure
(p = 0.02). No difference in
prosthesis failure rate between
shielded and unshielded
Chao et al. (2006) 84 Adjuvant THA RT: 7 Gy/1 (n = 38), HO development in 60% of Median F/U 20.5 months
6 Gy/1 (n = 20), 10 Gy/5 (n = 11), 6 Gy/3 patients receiving 6 Gy/3 (6.2–147)
(n = n = 8), 20 Gy/10 (n = 4), 20 Gy/5 compared to 13.8% for all other
(n = 1), 8 Gy/1 (n = 1), 6 Gy/2 (n = 1) dose fractionation schemes,
p = 0.01
Pakos et al. (2006) 55 Postoperative indomethacin (75 mg x 15 At 1 year post-op, 20.4% Mean F/U 1 year
days) and RT 7 Gy/1 after THA developed radiographical
incidence of HO, but only 1 had
clinically significant HO
Pohl et al. (2005) 315 Preoperative RT 7 Gy/1 evening before Immediately after and 6 months F/U immediately after
surgery post-op, 81.5% had no and 6 months post-op
development of HO, 16.8%
Brooker G1–2 (with significant
improvement in ROM), and 1.7%
G3–4 (no change in ROM)
Roth et al. (2005) 90 Adjuvant RT 15 Gy/5 (n = 14 within 5 No clinically relevant HO in any F/U 3, 6, and 12 months
days post-op), 7 Gy/1 (n = 13 within 24 h patients, with no significant post-op
post-op), and 7 Gy/1 (24 h pre-op) for difference among dose
prophylaxis fractionation schemes
Burd et al. (2003) 38 Patients randomized to adjuvant No effect of RT on the rate of Mean time to nonunion
indomethacin or RT 8 Gy/1 within 72 h long-bone nonunion. Indomethacin 5.3 months (3–11)
post-op for prophylaxis associated with increased rate of
nonunion (26 vs. 7%, p = 0.004)
Koelbl et al. (2003) 416 Pre-op RT 7 Gy/1 Overall HO incidence of 18.1% at F/U immediately and 6
F/U months post-op
Padgett et al. (2003) 29 (5 Gy/2) and 30 (10 Gy/5) Adjuvant THA RT of 5 Gy/2 vs. 10 Gy/5 No significant differences in HO Mean F/U for 5 Gy/2
within 96 h post-op development: 93% (5 Gy/2) vs. was 13 months (6–27)
97% (10 Gy/5), p = 0.086 and for 10 Gy/5 was 12
months (6–24)
Stein et al. (2003) 11 Adjuvant ORIF RT 7 Gy/1 within 72 h 27% with radiographic HO F/U 12 months
post-op formation but 91% had no No RT-related
functional limitations complications
Cornes et al. (2002) 14 Adjuvant 7 Gy/1 within 72 h post-op 93% fully mobile with 1 Very low F/U rate
recurrence on X-ray at 8 months
Schaffer and Sosner 2 males, 22 and 40 years 20 Gy No X-ray changes, improved Useful after bone formed
(1995) 200 cGy fx function in two cases
Healy et al. (1995) 94 patients 550 cGy vs. 700 cGy 63% relapse 550 cGy, 10% relapse Single-dose 700 cGy
700 cGy better

Seegenschmiedt et al. 84 patients 1 Gy pre-op <4 h prior to surgery 93%, 44 patients evaluated were Equal to date patient
(1994) Randomized pre-op vs. post-op 3.5 Gy to total of 5 fractions. Post-op 72 h improved. No significant comfort increased pre-op
balanced age, sex, location, etc. difference in two groups
Gregoritch et al. (1994) 124 patients Single dose 7–8 Gy No difference pre-op vs. post-op 4 hours before with 7
Pre-op 4 h; post-op 48 h 26% vs. 28% HBF Gy—ease of treatment
Linclau et al. (1994) 154 patients Zweymüller prosthesis only 48% HBF
51Rx = 1000 cGy, 5 cm depth 60% without irradiation
Seegenschmiedt et al 137 patients Patients randomized to 10 Gy/5 (n = 73), 91.5% positive results Nonsteroidal helped all
(1993a, b) Equal male and female 26–82 20 Gy/10 (n = 7), or 17.5 Gy/5 (n = 61) High dose and nonsteroidal best groups
years Rx less than 9 days after Rx
Durr et al. (1993) 10 patients (temporomandibular 10 Gy/5 fractions 69% prevented ectopic bone
joints) 87% improved
14–59 years 3 patients parotitis
DeFlitch and Stryker 33 patients 700 cGy/1Fx 5 patients—3 risk factors New HO outside field in
(1993) 20–79 years 1–5 days post-surgery 100% HO (heterotopic 18/33 patients, like 3 or
ossification) more risk factors
4/18 patients—2 risk factors, 44%
HO
6/10 patients—1 risk factor
0% HO
MacLennan et al. (1984) 58 patients (67 hips) 2000 rad in 10 fractions within 5 days Dramatic improvement
Average age 63 years in hip function.
Ages 44–80 years Complications in 15
18 females and 40 males
Parkinson et al. (1982) 51 patients (hips) 2000 rad in 10 fractions withing 4 days 98% did not develop
Mean age 64 years heterotopic bone
Ages 46–80
17 females and 34 males
Schwartz and Kagan 1 male, 51 years old Excision followed by 2000 rad in 10 Prevention of heterotopic
157
(1979) (Zygomatico-coronoid fractions bone formation

ankylosis) Patient had trismus
19-month follow-up
13 Heel Spur (Plantar Fasciitis) neus, plantar fasciitis, and heel spurs do not
appear to be causally related (Cutts et al. 2012)
Plantar fasciitis is the inflammation of the plantar (Unified Medical Language System - Concept
fascia of the foot, which causes pain at the bot- Unique Identifier C0149756).
tom of the heel. The cause of the inflammation Radiation dose of 3–8 Gy has been evaluated.
may be secondary to repeated injuries at the point Whereas pain relief has often been noted, ran-
of insertion of the plantar fascia to the medial domized studies did not observe a difference in
tubercle of the calcaneus of the heel. While comparing various dose fractionations. There is
symptomatic patients are often found to have also no randomized trial to compare RT vs. other
heel spur, bony osteophytes on the anterior calca- treatments.
Sex/
Zahnreich 22 3 Gy/6 with 140 kV orthovoltage Significantly improved function F/U 3 months
et al. (2020) or 6 MV linac as measured by calcaneodynia post-RT
score for orthovoltage (49.6 vs.
83.3 pre-RT and 3 months
post-RT, p = 0.017) and linac
(49.3 vs. 72.9 pre-RT and 3
months post-RT, p = 0.017). No
significant difference between
orthovoltage and linac
treatments
Kedzierawski 47 EBRT 6 Gy/1 with Co-60 or Complete response in 79% of F/U 1–129 months
et al. (2017) 6 MV photons patients. Persistent pain No RT-related
responded well to re-irradiation adverse effects
Prokein et al. 117 Patients randomized to 6 Gy/6 No significant difference in pain F/U 12 and 48
(2017) (over 3 weeks, 2 × 1 Gy fraction between the difference dose weeks post-RT
per week) vs. 6 Gy/12 (over 4 fractionation schemes No RT-related
weeks, 3 × 0.5 Gy per week) adverse effects
Niewald et al. 118 Patients randomized to 6 Gy/6 Pain: mean decline of VAS F/U 12–48 weeks
(2015) (over 3 weeks, 2 × 1 Gy fraction scores of 42 points (6 Gy/6) and No RT-related
per week) vs. 6 Gy/12 (over 4 55 points (6 Gy/12), no toxicities
weeks, 3 × 0.5 Gy per week) with statistical significance
6 MV photons
Uysal et al. 450 Co-60 8 Gy/2 Significant pain reduction: F/U min 1 year
(2015) median VAS pain score 8
(pre-RT, range 4–10) vs. 1
(post-RT, range 0–3), p < 0.05
Hautmann 101 Re-irradiation: 3 Gy/6 or Pain: significant reduction in Mean F/U 24
et al. (2014) 5–6 Gy/1–1.2 Gy fractions median NRS scores of 8 months
(pre-RT, IQR 6–9), 6
(immediately post-RT, IQR
5–7.5), 3 (6 weeks post-RT, IQR
1.75–6), 3.5 (12 weeks post-RT,
IQR 1–6), and 1 (6, 12, and 24
months post-RT, IQR 0–3).
p = 0.002 after 12 weeks, and
p < 0.0005 for all other
timepoints
Koca et al. 62 Co-60 8 Gy/1 Pain—complete response, Median F/U 28
(2014) partial response, and no months (22–35)
response in 58%, 21%, and 21%,
respectively
(continued)
Sex/
Hermann et al. 250 6 Gy/6 or 3 Gy/6 with field sizes Complete symptom remission, Mean F/U 11
(2013) of <36 cm2, 36 to <64 cm2, >64 partial remission, and no change months
to <74.2 cm2, and >74.2 cm2 in 38%, 32%, and 19% of
patients, respectively
No influence of RT dose
fractionation or field size on
treatment outcomes
Niewald et al. 66 Patients randomized to 6 Gy/6 Pain: significant mean decline of F/U 12 weeks, up
(2012) (over 3 weeks, 2 × 1 Gy fraction VAS scores of 43 points to 1 year
per week) vs. 0.6 Gy/6 (over 3 (6 Gy/6) and 20 points
weeks, 2 × 0.1 Gy fraction per (0.6 Gy/6), p = 0.001
week) with 4–6 MV photons
Heyd et al. 130 Randomized to 3 Gy/6 vs. 6 Gy/6 Significant reduction of pain F/U immediately
(2007) scores at 6 months, but no after, 6 weeks prior
significant difference from dose and 6 months
fractionation schemes post-RT
Miszczyk et al. 327 1–45 Gy/1–3 fractions Complete pain response, Mean F/U 74
(2007) adequate (>50% reduction), and months
partial (<50% reduction) were
48%, 21%, and 17%,
respectively.
No dose-effect relationship
found but suggests not to exceed
9 Gy total dose and 1.5 Gy/
fraction
Muecke et al. 502 5 Gy/10 (n = 100) 6 MV photons, Significant differences in Median F/U 26
(2007) 5–6 Gy/5–6 (n = 140) 6 MV pain-free probability in months (1–103)
photons, 5 Gy/5 (n = 101) 10 MV multivariate analysis for
photons, 6 Gy/6 (n = 161) high-voltage RT vs. orthovoltage
175 kV RT, p = 0.05, HR 1.51 (95% CI
1.0–2.28)
Schneider 62 5 Gy/7 fractions with 10 MV Pain: significant reduction in F/U immediately
et al. (2004) photons VAS pain score 6.3 (pre-RT) vs. after, 6 weeks, and
3.8 (immediately after), 28 and 40 months
p < 0.001, with overall post-RT
continued pain relief at
long-term F/U
Schwarz et al. 6 8 Gy/1 67% had complete pain relief Mean F/U 15.6
(2004) months (1.5–30)
Mucke et al. 117 5 Gy/10 with 6 MV photons 2 Pain: complete resolution, Mean F/U 20
(2003) fractions/week marked improvement, slight months
improvement, and no change
experienced by 23%, 34%, 27%,
and 16%, respectively
14 Osteoblastoma/Osteoid ondary to this entity may be less well controlled

Osteoma by nonsteroidal anti-inflammatory drug than
osteoid osteomas. Surgical removal is one of the
These are benign neoplasms of the bone. They treatment modalities for these benign bone
are made up of osteoid tissue and large osteoblast- lesions. Following surgery, recurrence rates of
like cells that form well-circumscribed lytic 18–23% have been observed. The role of radio-
lesions of various sizes. They are frequently therapy is controversial and the histologic diag-
found in young adult men and could be painful. nosis difficult. There are reports suggesting the
Osteoid osteomas tend to occur in long bones and possibility of transformation of osteoblastoma
are often managed conservatively using nonste- into osteosarcoma, implicating irradiation. The
roidal anti-inflammatory drugs. Other treatments available literature is small, and we are unable to
include surgery and radiofrequency ablation. A confirm a causal relationship with irradiation.
phase 3 randomized trial is underway comparing These lesions commonly occur in the vertebral
magnetic resonance-guided focused ultrasound column and skull, making complete surgical
ablation (MRgFUS) vs. computed tomography- excision difficult. Radiation in high doses (50 Gy)
guided radiofrequency ablation of osteoid oste- has been associated with long-term control in
oma (clinicaltrials.gov NCT02923011). nonresected lesions (Atesok et al. 2011; Versteeg
Osteoblastoma is a rare primary benign entity et al. 2017) (NCI Thesaurus Code: C3294).
that more frequently affects the spine. Pain sec-
Total # of
patients
receiving
Author, year RT Diagnosis Treatment Results Notes
Jiang et al. 11 Osteoblastoma Intralesional 82% experienced Median F/U 75 months
(2015) curettage recurrence (14–148)
followed by RT
40–45 Gy
Yin et al. 9 Osteoblastoma Subtotal resection 66.7% relapsed Mean F/U 45.8 months
(2014) with RT (18–128)
30–50 Gy in 20
fractions
Boriani 5 Osteoblastoma 40–44 Gy No evidence of Mean F/U 76 months
et al. recurrence (39–167)
(2012)
Poleskic 6 Osteoblastoma Adjuvant RT of 12.5% relapse in a Median F/U 26 years
et al. 46 Gy given to total of 64 patients. (6–420 months)
(2010) recurrent tumors No results on patients
(n = 6). No who received RT
fractionation
stated
Singer and 1 male Osteoblastoma. XRT—50 Gy/25 In 6 months, pain
Deutsch Petrous temporal fractions, wedged and bleeding
(1993) bone, 16 years pair technique resolved. CT after 10
years showed
persistent
radiographic
abnormality; no
expansion
(continued)
Total # of
patients
receiving
Author, year RT Diagnosis Treatment Results Notes
Capanna 2 Osteoblastoma Curettage and Disease free at 9- and
et al. and osteoid radiotherapy 25-year follow-up
(1986) osteoma.
Sacrum, ages 17
and 20 years
Mitchell 2 Osteoblastoma Curettage, XRT, Palliation of pain, but Difficulties in
and Ilium, age 15 6000 rad no tumor response. differentiating
Ackerman years Died with metastatic histologically:
(1986) osteosarcoma osteoblastoma,
aggressive
osteoblastoma and
osteoblastoma-like
osteosarcoma, osteoid
osteoma
Femur, age 12 Excision local Symptoms
years recurrence. decreased. No
Rebiopsy 2500 evidence of disease
rad/2 weeks at 14-year follow-up
Jackson 18 Recurrent 1. Re-excision 1. Only 2 remained Review article
(1978) osteoblastoma only (n-7). recurrence free, 2
2. Re-excision died within 5 years;
with RT (n = 3). no F/U for
3. RT only remaining.
(n = 3). 2. One patient
4. Missing data required re-excision,
(n = 5). with remainder
No dose/ recurrence free.
fractionation 3. Two required
given re-excision
15 Pigmented Villonodular deteriorations. This pathologic condition was

Synovitis (Tenosynovial first described in 1941. Standard therapy is com-
Giant Cell Tumor) plete excision, but the recurrence rates are as
high as 45%. In relapsing cases and in some
Pigmented villonodular synovitis or diffuse instances to avoid mutilating surgery, radiother-
tenosynovial giant cell tumor is a proliferative apy is indicated—35 Gy/15 fx being a com-
process affecting joints and tendon sheaths. They monly recommended dose (NCI Thesaurus
are composed of synovial-like mononuclear Code: C3401). Apart from external radiotherapy,
cells, hemosiderin-laden macrophages, foam intra-articular injection of radionuclide, such as
cells, and inflammatory cells. Most often, the yttrium 90, may also be added. In August 2019,
knee and hand are the affected sites, but any the US Food and Drug Administration approved
synovial sheath may be involved. Pigmented vil- the use of pexidartinib, a colony-stimulating fac-
lonodular synovitis can form nodules or dif- tor 1 receptor inhibitor, as a systemic option to
fusely affect the entire lining of the joint. These the treatment of symptomatic tenosynovial giant
tumors at the joint can cause edema, pain, restric- cell tumor based on the ENLIVEN phase 3 trial
tions in joint movements, joint locks, and joint (Tap et al. 2019).
Total # of
Guo et al. 26 Adjuvant arthroscopic ± Significant improvement as Median F/U 54
(2018) open synovectomy or RT measured by median AOFAS (15–108)
20/10 with 6 MV photons scores of 75 (pretreatment) vs. 97
3–4 weeks post-op (posttreatment), p < 0.05
Mollon et al. 11 Adjuvant RT with 13% (n = 2) experienced Mean F/U 81
(2016) 35 Gy/14 or 48 Gy/24 symptomatic recurrence. No months
RT-specific data
Li et al. 26 Adjuvant EBRT Significant pre- and posttreatment Mean F/U 54
(2015) 20–30 Gy/10 improvement in Lysholm knee months (24–72)
function scores (54.3 vs. 71.2,
p < 0.01)
Bruns et al. 8 Adjuvant RT. No dose No recurrence if adjuvant therapy
(2013) fractionation described treating primary disease. After at
least one recurrence, further
recurrences were observed
Chen et al. 19 Adjuvant RT 30 Gy/10 Significant improvement of knee Median F/U 98
(2012) flexion, extension, and mean months (42–143)
Tegner-Lysholm knee scores from No RT-related
59 (pretreatment) to 93 toxicities
(posttreatment), p < 0.001
de Carvalho 8 Adjuvant EBRT mean No evidence of radiographic Mean F/U 8.6 years
et al. (2012) 20 Gy (range progression. Only 1 (12.5%) had
10–36.4 Gy)/10 disease recurrence during F/U
Park et al. 23 Adjuvant EBRT median Median disease-free survival of 5 Median F/U 9 years
(2012) 20 Gy (range 12–34)/10 years. 17.4% developed (0.8–12)
with 4 or 6 MV photons recurrence No >3 RT-related
Total RT dose not predictive of toxicities and no
local control on univariate RT-induced
analysis malignancies
Heyd et al. 41 Adjuvant RT median Local control in 95.1%. 82.9% F/U range 6
(2010a, b) 36 Gy (30–50 Gy) in had no or slight functional months–10 years
median 2 Gy fractions impairment No >G2 RT-related
toxicity
Horoschak 17 Adjuvant RT mean 34 Gy Local control achieved in 75% Mean F/U 46
et al. (2009) (range 20–36) with with mean time to recurrence of months (8–181).
4–15 MV photons 38 months. Repeat resection No >G2 RT-related
resulted in 100% local control toxicities
thereafter (mean F/U 61 months)
Nassar et al. 12 Adjuvant EBRT No evidence of disease recurrence Mean F/U 27
(2009) 26–30 Gy/2 Gy fractions or progression of bony months (20–36).
6–8 weeks post-op destruction No RT-related
toxicities
Berger et al. 7 Adjuvant RT 30–50 Gy No evidence of recurrent or Mean F/U 29
(2007) with 6 MV photons persistent disease at F/U with months (3–112).
86% (n = 6) having excellent limb No RT-related
function toxicities
O’Sullivan 41 Adjuvant RT mean dose Only 1 patient had active disease Mean F/U 77
et al. (2005) 38 Gy (range 28–50 Gy); at F/U months (13–337).
most common dose/ No RT-related
fraction 35 Gy/14 toxicities or
secondary
malignancies
Lee et al. 7 Adjuvant RT 35 Gy/20 86% (n = 6) reported improved Mean F/U 24
(2005) function and reduced pain. No months (18–36)
evidence of recurrence
(continued)
Total # of
Brien et al. 4 Adjuvant RT No evidence of recurrence Mean F/U 9 years
(2004) 36–40 Gy/20–25
fractions
Chin et al. 5 Adjuvant RT Overall, pre- and posttreatment Mean F/U 5 years
(2002) 35 Gy–45/15–20 patients had improved ROM and (1.5–8)
fractions 3 months Knee Society scores (61 vs. 92,
post-op p < 0.001)
O’Sullivan 14 35 Gy/15 fx 13/14 responded 11 good to
et al. (1995) excellent, 3 fair
results, no
amputations
required
Gitelis et al. 1 patient, Surgery in all cases Hip improved Radiation used in
(1989) 64 cases including 13 irradiated incomplete excision
reviewed patients or recurrence
Franssen 8 185 MBq 90yttrium 4 improved No complications.
et al. (1989) silicate 2 cartilage damage All had some
histologic synovitis
Friedman 1 patient 2000–3000 Roentgens Response
and 9 literature
Schwartz cases
(1957)
Greenfield 5 Orthovoltage 200 kV, Favorable response
and Wallace 1500–2400 Roentgens 2 histologic improvements shown
(1950)
15.1 Radionucleotides
Total # of
Gortzak et al. 56 Synovectomy ± 90Y intra-articular No significant difference in Mean F/U
(2018) injection (n = 34) disease recurrence 7.3 years
Shabat et al. 10 90
Y intra-articular injection 6–8 weeks No evidence of disease Mean F/U
(2002) post-debulking surgery progression. 6 years
No complications
16 Plantar Fibromatosis, Peyronie’s disease, suggesting the presence of a

Ledderhose Disease common hereditary pattern among these condi-
tions. Many individuals with Ledderhose disease
The term fibromatosis defines an infiltrating do not experience symptoms and are not diag-
fibroblastic proliferation showing none of the nosed. Some evolve to larger lesions that cause
features of an inflammatory response and no fea- gait changes and pain when walking. Repeated
tures of neoplasia. Plantar fibromatosis refers to trauma, long-term alcohol consumption, chronic
the formation of fibromatosis of the plantar fascia liver disease, diabetes, and epilepsy have been
characterized by thickening of the fibrous bands reported in association with the development of
on the plantar aponeurosis in the sole of the foot this condition. Subjective improvements in pain
and toes and is often called Ledderhose disease. are reported following radiotherapy, prescribed
This condition is often associated with similarly to Dupuytren’s contracture (NCI
Dupuytren’s contracture (see that section) and Thesaurus Code: C4680).
Total #
of
Banks et al. 10 6 MeV electrons Significantly improved Median F/U 4.5 months
(2018) 30–36 Gy/10–12 performance (78.9– (1.5–10.4)
fractions (3 Gy/ 84.6, p = 0.007),
fraction) split course reduced pain (3.0–1.1,
with 3-month break p = 0.0001), and
in between reduced volume on
MRI (1.5–1.2 cm3,
p = 0.01)
Schuster et al. 33 21 Gy/7 or 30 Gy/10 Pain: 81% reduction in Median F/U 31 months.
(2015) with 6–12 MeV pain and burning No >G2 late toxicities
electrons sensation
Local control rate 83%
Heyd et al. 24 Orthovoltage or 33.3% complete Median F/U 22.5 months.
(2010a, b) electrons 15 Gy/5 remission, 54.5% No >G2 skin/soft tissue toxicity
fractions × 2 with 6 reduction in size, and
weeks in between 12.1% unchanged. Pain
relief in 68.4% with
improved gait in 73.3%.
No disease recurrence
de Bree et al. 6 Adjuvant RT 60 Gy All recurrence free Median F/U 20 years (2–26).
(2004) except 1 that had RT-related impaired healing
positive margins requiring amputation (n = 1) and 2
(recurred within 6 cases of invalidating foot
months) dystrophy
Seegenschmiedt 25 15 Gy/5 twice, 8–12 44% had reduction in Median F/U 38 months (12–67).
and Attassi weeks apart nodule number or size, No patient had progression. No
(2003) 54% had reduction in grade 3 or 4 toxicity
number or length of
cords, 50% had
improved gait, 60% had
reduced pain.
80% reported improved
condition. Median VAS
improvement was 50%
Stockdale et al. 56 1. 11—surgery 3—relapsed With musculoaponeurotic
(1988a, b) 2. 29—surgery and 7—relapsed fibromatosis.
post-op radiotherapy Variable response Relapses associated with doses
3. 16—radiotherapy <50 Gy
Stout (1954) 3 Excision 2/3 recurred at 6 months All three cases were previously
in 1 and at 7 years in reported by Pickren. Authors
the other stated that such growths remain
small and symptomless and should
probably be ignored after biopsy
to prove that they are not
malignant
Pickren et al. 16 Local excision (14) 13/14 recurred at 2
(1951) weeks to 4.5 years
17 Baker’s Cyst (Herman and Marzo 2014; Frush and Noyes

2015) (NCI Thesaurus Code: C34935). One pro-
Baker’s cyst is a fluid-filled mass at the back of spective study observed a reduction in the vol-
the knee, within the popliteal fossa, specifically ume of the cyst along with improved joint
at the gastrocnemius-semimembranosus bursa functions.
Total # of
Hautmann 20 knees 3.0 Gy in 0.5 Gy/ >25% decrease in Baker’s cyst volume in Baker’s cyst
et al. (2019a, (18 fractions (n = 8) and 75% and 79% of patients at short (6–12 arising from
b) patients) 6.0 Gy in 1.0 Gy/ weeks) and long term (9–12 months) F/U, RA
fractions (n = 12) respectively
18 Thalassemic Arthropathy the early development of degenerations. Another

potential cause to the development of arthropathy
With improving longevity of patients with thalas- in thalassemic patients is the use of the iron che-
semia, long-term complications are being lator, deferiprone (Berkovitch et al. 1994), which
observed in bones and joints (Gratwick et al. alters the deposition of iron within the skeletal
1978; Piga 2017). Akin to other organ dysfunc- and joint structures (Noureldine et al. 2018). The
tions in thalassemic patients, arthropathy may be use of radiotherapy has largely not been evalu-
secondary to iron overload at the joints leading to ated in this condition.

Papavasiliou et al. (1992) 1 6 Gy Complete resolution
Amini A, Yahyanezhad S, Velez E, Gholamrezanezhad

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Treatment and outcome of malignant giant cell tumor
Neurological Disorders
Christian Iorio-Morin,
Samuelle-Arianne Villeneuve,
Contents Neurological disorders form a diverse group of

1 Essential Tremor 182 entities including autoimmune, degenerative,
vascular, traumatic, congenital, and oncological
2 Mesial Temporal Lobe Epilepsy 184
processes. Neurological symptoms arise when a
3 Hypothalamic Hamartomas 184 specific neural network is affected. As such, a
4 Epilepsy (Corpus Callosotomy) 188 symptom (e.g., tremor) can result from multiple
References 189
diseases (e.g., essential tremor, Parkinson’s dis-
ease, multiple sclerosis, trauma) and multiple
symptoms (e.g., tremor, pain, seizures) can arise
from a single event (e.g., traumatic brain injury).
While most of the aforementioned processes can-
not be reversed or cured, neurological symptoms
can often be improved by interfering with the dis-
eased neural network. This field is called func-
tional neurosurgery and typically involves
inactivation of a specific target via either con-
trolled lesioning or surgical implantation of elec-
trodes (e.g., deep brain stimulation (DBS), vagal
nerve stimulation (VNS), spinal cord stimula-
tion). Lesioning can be accomplished through
multiple modalities including open surgery,
radiofrequency thermocoagulation (RF), laser
interstitial thermal therapy (LITT), focused ultra-
sounds (FUS), or stereotactic radiosurgery (SRS).
This chapter reviews the results of SRS for the
C. Iorio-Morin · S.-A. Villeneuve · D. Mathieu alleviation of tremor as well as three epileptic
Division of Neurosurgery, Department of Surgery, syndromes: mesial temporal epilepsy, hypotha-
Université de Sherbrooke, Sherbrooke, QC, Canada
e-mail: christian.iorio-morin@usherbrooke.ca; lamic hamartoma, and refractory generalized sei-
samuelle.villeneuve@usherbrooke.ca; zures. SRS for the treatment of pain is reviewed
david.mathieu@usherbrooke.ca in a dedicated chapter.
L. Masson-Côté (*) The involvement of a multidisciplinary team
Division of Radiation Oncology, Department of is critical whenever the treatment of a neurologi-
Nuclear Medicine and Radiobiology, Université de cal disorder is contemplated. A neurologist
Sherbrooke, Sherbrooke, QC, Canada
e-mail: laurence.masson-cote@usherbrooke.ca specialized in movement disorders or epilepsy

182 C. Iorio-Morin et al.
should always confirm the diagnosis and certify receiving fibers from the cerebellum. This can be
that all medical options have been exhausted. The accomplished using DBS, where high-frequency
various surgical options, including neuromodula- stimulation will inhibit the nucleus, or by creat-
tion and lesioning approaches, should be ing a lesion centered on the nucleus, which is
explained to the patient by a functional neurosur- called a thalamotomy. The ideal thalamotomy
geon involved in treatment planning. Whatever lesion is 7–9 mm large and typically results in a
the chosen modality, outcomes depend more on 50–75% reduction in contralateral tremor. Side
patient selection and proper targeting than on the effects emerge when the lesion encroaches on
specific means by which the target is stimulated adjacent structures, such as the internal capsule
or lesioned. Neuromodulation approaches, such laterally (hemiparesis), the dentatorubrotha-
as DBS for tremor, have the advantage of being lamic tract inferiorly (ataxia and gait distur-
adjustable as the disease progresses, though they bance), or the ventralis caudalis (Vc) nucleus of
require permanent implantation of hardware, fre- the thalamus posteriorly (paresthesia/anesthe-
quent programing sessions, and battery replace- sia). As such, lesion size and location are criti-
ment. Lesioning approaches are inexpensive and cal. Because the Vim cannot be directly
do not require support or regular follow-up over visualized on conventional MRI sequences, tar-
the long term but are irreversible once performed. geting is performed using atlas-based coordi-
Within the lesioning modalities, SRS is the only nates relative to the anterior and posterior
one not requiring interruption of antithrombotic commissures and the wall of the third ventricle.
medication. It does not require an incision and During DBS surgery or RF thalamotomies, intra-
brain penetration (unlike RF and LITT) and does operative stimulation is used to confirm the pre-
not require complete head shaving (unlike FUS). sumptive target location. During FUS
The main disadvantage of SRS is that the target thalamotomies, reversible lesions at low temper-
cannot be physiologically confirmed before per- ature are first performed to ensure adequate tar-
forming the definitive lesion. It also has a delayed geting. When the lesion is performed using SRS,
onset of action and can cause inflammatory however, no such intraprocedural validation can
adverse radiation effect, the clinical manifesta- be obtained and clinical benefit is observed on
tion of which will depend on the location of the average 5 months after the intervention
target. (Martínez-Moreno et al. 2018). Perhaps for these
reasons, adoption of SRS for tremor has been
slower than other modalities such as FUS, even
1 Essential Tremor though extensive evidence supports its equiva-
lent efficacy and likely better safety profile
Essential tremor is the most frequent movement (Iorio-Morin et al. 2021).
disorder, affecting 5% of adults over 65 years old Table 1 details the series of SRS thalamoto-
(Louis and Ferreira 2010). It is a disease resulting mies for essential tremor reporting >10 patients.
in excessive cerebellar output to the motor thala- Note that most procedures were performed uni-
mus, which generates an action tremor, typically laterally, but that second-side treatments are
in the upper extremities, head, and vocal cords. increasingly being performed and appear to be
While most cases are mild and can be controlled equally safe and effective (Niranjan et al. 2018;
with medication, many patients eventually Young et al. 2010, 2014). While these results
become disabled by the tremor. When it starts were generally obtained in essential tremor
interfering with activities of daily living (button- patients, other tremor syndromes, such as
ing a shirt, drinking with one hand, cutting food, Parkinson’s disease and multiple sclerosis-
etc.), surgical procedures can be considered. associated tremor, can also be treated with thala-
The goal in tremor surgery is inhibition of the motomies, although the functional benefit might
ventralis intermediate nucleus (Vim) of the thal- vary. When carefully planned and successfully
amus, which is a 3 mm wide shell of neurons executed, the radiosurgical treatment of tremor
Neurological Disorders 183
Table 1 Series of radiosurgery (>10 patients) for essential tremor

Complications/
Author, year Patients Target Maximal dose Results Follow-up time comments
Ochiai (2021) 17 Vim 130 Gy 64% tremor 24 months 12% mild
improvement hemiparesis
Perez- 13 Vim 130 Gy 64% tremor Minimum—12 months 27% adverse
Sanchez improvement events
(2020) 11 of 13 patients
had improvement
of quality of life
Niranjan et al. 73 Vim 130–150 Gy 60% tremor Median: 28 months 4% transient
(2017) improvement adverse radiation
effects
Witjas et al. 50 Vim 130 Gy 54.2% tremor Mean—12 months 2% hemiparesis
(2015) improvement
72.2%
improvement in
quality of life
Kooshkabadi 86 Vim 130–140 Gy 81% tremor Mean—11.5 months 5% adverse events
et al. (2013) improvement including
hemiparesis,
dysphagia, and
facial numbness
Ohye et al. 72 Vim 130 Gy 81% excellent/ 24 months No major
(2012) good outcome on complication
UPDRS
Mark et al. 196 Vim 140 Gy 82.6% tremor Mean—84 months 3% adverse events
(2011) improvement including
hemiparesis and
speech difficulty
Lim et al. 14 Vim 130–140 Gy 21% tremor Mean—19.2 months 7% recurrence
(2010) improvement rate
11 of 14 patients 21% adverse
had improvement events including
in quality of life thalamic
hemorrhage,
numbness
Young et al. 161 Vim 141–152 Gy 81% tremor Mean—44 months 7% adverse events
(2010) improvement including sensory
loss, hemiparesis,
and speech
disturbances
Duma et al. 38 Vim 130 Gy 90.5% tremor Mean—30 months 5.2% recurrence
(1999) improvement rate
2.6% dysarthria
Friedman 15 Vim 120–140 Gy 100% tremor Range—3–8 months 47% adverse
et al. (1999) improvement events including
transient slowed
fine finger
movements,
action tremor,
symptomatic
edema
a
When multiple papers reported results from the same patients, only the paper with the largest cohort and/or longest
follow-up was included
can provide spectacular results. The positive Because quality of life was more associated with
impact on the patient’s quality of life cannot be seizure reduction than with adverse effects, sur-
overstated. gery remains the preferred treatment in most cen-
ters. Interestingly, similar inferior results were
obtained when comparing selective amygdalohip-
2 Mesial Temporal Lobe pocampectomy to anterior temporal lobectomy
Epilepsy (Josephson et al. 2013; Hu et al. 2013), suggesting
that it is the extent of tissue targeted rather than
Mesial temporal lobe epilepsy (MTLE) is a fre- the ablative technique that is driving the outcome.
quent epileptic syndrome, most often secondary Many groups are now investigating other mini-
to hippocampal sclerosis. It typically manifests as mally invasive alternatives, such as LITT or FUS,
focal onset seizures in which the patient initially which are showing efficacy similar to SRS
experiences a sense of déjà vu, anxiety, fear, (Grewal et al. 2018; Wang et al. 2021). Therefore,
unusual smell, or rising sensation from the stom- when considering an intervention for MTLE, the
ach to the chest. Patients then go on to have first issue to address is whether the patient should
impaired awareness and can develop secondary undergo an anterior temporal lobectomy or a
generalization leading to tonic-clonic movements. more selective intervention on the medial struc-
Unlike many other types of epilepsy, MTLE can tures. If the latter option is selected, SRS is an
be cured by surgical interventions removing the excellent modality providing a noninvasive, non-
seizure-onset zone, with multiple randomized operative solution, at the cost of a latency period
controlled trials demonstrating the superiority of which can reach 24 months. Despite not achieving
various resection protocols (e.g., anterior tempo- seizure freedom in all patients, quality of life can
ral lobectomy, selective amygdalohippocampec- still be improved by reducing seizure burden.
tomy, parahippocampectomy) compared to best Table 2 summarizes all series (>4 cases) of SRS
medical management (West et al. 2019). As such, for mesial temporal epilepsy.
temporal lobe resection is recommended by the
American Academy of Neurology as the proce-
dure of choice (Engel et al. 2003). Yet, studies 3 Hypothalamic Hamartomas
have shown that it remains underutilized within
eligible patients, presumably because of the risk Hypothalamic hamartomas are developmental
of adverse events (11%), which include cognitive malformations located within the hypothalamus
disturbances (6%) and neurological deficits (3%) area that can extend to the third ventricle and
(Engel et al. 2003). suprasellar region. While they are nonprogres-
Radiosurgery has been proposed as a noninvasive, they exhibit intrinsic epileptogenic activity
sive alternative to open resection with the ratio- that can produce multiple seizure types that
nale that it could have a lower complication rate. evolve over time. Patients typically present first
The ROSE trial, a randomized controlled trial with gelastic seizures (laughing spells lasting
comparing SRS to anterior temporal lobectomy, <30 s) starting around 1 year of age. Additional
was completed in 2018 and demonstrated an seizure subtypes then appear, including tonic-
acceptable safety profile, but a lower efficacy for clonic seizures, drop attacks, and atypical
SRS (Barbaro et al. 2018). Seizure freedom was absences that are often medically intractable.
achieved in 52% of SRS cases compared to 78% Cognitive impairment is observed in nearly 50%
of surgical cases, while both groups showed a of cases, and many patients also display psychiat-
decline in verbal memory (36% vs. 57%) and ric, behavioral, and endocrinological symptoms.
visual field defects (34% vs. 42%), and 65% of Open surgical resection of the hamartoma
SRS patients required temporary steroid use. can cure the epilepsy in 54% of cases, but the
Table 2 Series of radiosurgery for mesial temporal epilepsy
Author, year Patients Target Dose planning Results Follow-up time Complications/comments
Barbaro 31 Amygdala, anterior 2 cm of hippocampus, 24 Gy at the 50% 52% seizure 36 months 39% adverse events including
(2018) parahippocampal gyrus isodose remission headaches, transient neurological
Target volume: deficits, and transient
5.5–7.5 cm3 exacerbations of seizures
Wang (2017) 37 Edges of amygdaloid nucleus and 19 Gy at the 50% 73% seizure NS 8% “mental” symptoms
Neurological Disorders
hippocampal area and edges of forehead and isodose remission 3% “extradural hematoma”
anterior temporal lobe Target volume 3% memory decline
average: 5.31 cm3
Usami (2012) 7 Amygdala, hippocampal head, and body, 18 Gy (2 patients) 29% seizure NS 29% symptomatic radiation
most of the parahippocampal gyrus and the and 25 Gy (5 remission necrosis
entorhinal cortex patients) 14% death due to seizure
At the 50% isodose 14% headache and edema
14% gait disturbance
Kawamura 11 Anterior 2.5 cm of the hippocampus, the 20–25 Gy to the 36% seizure > 9 years 9% death due to seizure
(2012) amygdala, and parahippocampal gyrus 50% isodose remission 9% cognitive impairment,
Target volume: aphasia, and right hemiparesis
4.8–17.1 cm3 9% severe headache, visual
changes with quadrant
hemianopsia, and frequent
partial seizures
9% cognitive impairment and
left hemiparesis
Liang (2010) 7 Anterior 8 cm of lateral temporal cortex and 12 Gy at the 85% 0% seizure 24 months 29% transient complications
4–6 cm of mesial structures, including the isodose line remission (nausea or headaches)
amygdaloid complex (sparing the upper and (fractionated 29% IQ drop, memory decline,
mesial part), head and body of the Linac) and permanent neurologic
hippocampus, and anterior part of the complications (partial aphasia
parahippocampal gyrus and mild hemiplegia, progressive
ataxia, and cognition decline)
Barbaro 30 Amygdala, anterior 2 cm of hippocampus, 20 Gy (13 patients) 67% seizure 36 months 63% headache
(2009) parahippocampal gyrus or 24 Gy (17 remission (77% in 56% edema
patients) at the high-dose group 50% visual disturbance
50% isodose vs. 59% in 15% verbal memory decline
Target volume: low-dose group)
5.5–7.5 cm3
(continued)
185
Table 2 (continued)
186
Author, year Patients Target Dose planning Results Follow-up time Complications/comments
Vojtek (2009) 14 Amygdala sparing the superior and mesial 20 Gy at the 50% 7% seizure >60 months 64% controlled edema
part, to the head and anterior half of the body isodose remission 14% quadrantanopia
of hippocampus, and to the anterior part of Mean target 14% psychotic episodes
the parahippocampal gyrus volume: 6.764 cm3 14% status epilepticus
Rheims 15 Anterior part of the parahippocampal region, 21 Gy at the 50% 47% seizure Mean: 27% transient increase in seizure
(2008) entorhinal area adjacent to the collateral isodose remission 60 ± 22.3 months rate between 9 and 18 months
sulcus and rhinal sulcus, head of the 27% transient increase in aura
hippocampus, anterior part of hippocampal between 9 and 18 months
body, amygdalofugal part of the amygdaloid 53% headaches maximal
complex between 9 and 18 months
13% asymptomatic superior
quadrantanopia
Hoggard 8 Amygdala, head, and anterior half of the 25 Gy at the 50% 38% seizure 24–53 months 25% exacerbation of symptoms
(2008) hippocampus body, anterior half of the isodose remission between 6 and 12 months
parahippocampal gyrus Target volume: 25% experienced changes in
6.2 ± 0.7 cm3 their seizures (e.g., attack
clusters, new drop attacks)
25% headaches at 12–18 months
No visual field disturbances
Bartolomei 15 Anterior parahippocampal region, entorhinal 24 Gy at the 50% 60% seizure 72–120 months 60% mild headaches
(2008) area adjacent to the collateral and rhinal isodose remission 59% visual field deficits
sulci, head of the hippocampus, anterior part
of hippocampal body, and amygdalofugal
part of the amygdaloid complex
Régis (2004) 21 Anterior parahippocampal cortex, basal and 24 Gy at the 50% 65% seizure 2 years 25% transient side effects:
lateral part of amygdala, and anterior isodose remission headaches, depression, nausea,
hippocampus vomiting, and imbalance
45% visual field deficits
Srikijvilaikul 5 Anterior hippocampus from back to 20 Gy 50% isodose 0% seizure 20 months 40% death (resulting from
et al. (2004) midbody, amygdala, parahippocampal gyrus Target volume: remission seizures)
7.3 cm3 20% headaches
C. Iorio-Morin et al.
depth and proximity of the lesion to the hypo- attained in 44% of cases on average, which is
thalamus, mamillary bodies, and fornix make slightly lower than that for other modalities and can
the surgery at high risk of complications (espe- take up to 3 years to achieve. However, SRS seems
cially short-term memory deficits seen in 58% safer than other modalities with few reported com-
of cases and persisting long-term in 8%) (Ng plications. This is likely because SRS provides a
et al. 2006). RF ablation and LITT have been more conformal coverage of the hamartoma than
used as simpler alternatives to resection with a RF and LITT, which are limited by insertional tra-
similar efficacy (69% (Kondajji et al. 2021) and jectories and ventricles acting as heat sinks. As
49% (Du et al. 2017) seizure freedom, respec- such, SRS is an ideal first-line modality for stable
tively) and different safety profiles (less mem- patients who can tolerate seizures during the
ory impairment, but more hypothalamic latency period. RF, LITT, and surgery can be per-
complications, such as endocrine, hyperphagic, formed as a second-line intervention if seizure con-
and autonomic disturbances). trol is not achieved, or as a first-line treatment in
Multiple series have shown that radiosurgery large or severe cases where the requirement for
can successfully treat epilepsy associated with immediate seizure cessation outweighs the
hypothalamic hamartomas. Seizure freedom is increased risk of complications (Table 3).
Table 3 Series of radiosurgery for hypothalamic hamartoma

Author, Technical Follow-up Complications/
year Patients details Dosing Results time comments
Hamdi 39 Gamma knife 17 Gy (14–25 Gy) 44% seizure 71 months No complication
et al. at the 50% freedom 46% had
(2021) (35–60%) isodose improvement of
Mean target working memory
volume: 0.48 cm3
Romanelli 2 Cyberknife 16 Gy at the 65% 100% seizure 10 years No complication
(2018) or 70% isodose freedom
Target volume:
11.5 cm3 and
8.9 cm3
Régis 57 Gamma knife 17 Gy (14–25 Gy) 40% seizure 71 months 6.2% transient
et al. at the 50% freedom poikilothermia
(2017) (35–60%) isodose 16.6% transient
Mean target increase in seizure
volume: 0.40 cm3 frequency
Drees 4 Gamma knife 18 Gy at the 50% 50% seizure 70 months 25% weight gain
et al. isodose freedom
(2012) Mean target
volume: 0.54 cm3
Mathieu 9 Gamma knife 14–20 Gy at 50% 67% seizure free 36 months No complication
et al. 6 patients with for the HH (HH treatments)
(2010) HH treatment treatments 0% seizure free
3 patients with 15–16 Gy at 50% (HH
disconnection for the disconnections)
attempts disconnections
Abla et al. 10 Gamma knife 18 Gy (16–20 Gy) 60% seizure 43 months 10%
(2010) at the 50% isodose freedom poikilothermia
Mean target 10% depression
volume: 0.70 cm3 20% weight gain/
increased appetite
10% anxiety
Mathieu 4 Gamma knife 17.5 Gy at the 0% seizure 22 months No complication
et al. 50% isodose freedom
(2006) Mean target 50% Engel II
volume: 0.37 cm3
4 Epilepsy (Corpus nection syndrome characterized by unilateral

Callosotomy) anomia, agraphia, alexia, apraxia, and alien
hand. As such, many authors typically target
In some patients, seizures have bilateral, multi- only the anterior two-thirds of the bundle,
focal origins and cannot be addressed by surgi- although posterior completion can be per-
cal ablation of a unique seizure-onset zone. This formed as a second stage if seizures remain
often happens in genetic syndromes, such as generalized.
Lennox-Gastaut, or from metabolic etiologies. Callosotomies are classically performed
In these patients, when seizure control is unat- through open surgery, which requires hospital
tainable with medication, disconnection proce- admission and is associated with a risk of
dures can be offered to limit the spread of meningitis, hydrocephalus, hematoma, and
discharges from one brain region to another. stroke. Multiple groups have now attempted
While disconnections do not necessarily radiosurgical corpus callosotomies and dem-
decrease seizure frequency, they can improve onstrated a good safety and efficacy profile.
quality of life by preventing secondary general- Like for all radiosurgical interventions, a
ization and their clinical manifestation, such as latency period is to be expected. Table 4
drop attacks with resulting unprotected falls and describes all published series (>1 patient) of
head trauma. radiosurgical corpus callosotomy. This proce-
Corpus callosotomy is a type of disconnec- dure should only be performed after a thor-
tion procedure in which the corpus callosum ough epilepsy workup has ruled out a focal
is sectioned to impede the spreading of unilat- origin and other, reversible palliative treat-
eral seizures to the contralateral side. ments such as DBS or VNS have been consid-
Complete callosotomy can lead to a discon- ered and rejected.
Table 4 Series of radiosurgical corpus callosotomy

Dose Mean
Author, year Patients Technical details planning Results follow-up time Complications
Feichtinger 8 Target: 6 120 Gy 37.5% drop attacks 60 months 25% transient
et al. patients max completely abolished headache
(2006) anterior Mean target 25% significant reduction 25% edema
callosal volume: of drop attack
disconnection, 0.414 cm3 25% complete reduction
2 patients of generalized tonic-
posterior, 1 clonic seizure
patient middle 50% reduction of more
than 50% of generalized
tonic-clonic seizures
Eder et al. 3 All patients 120 Gy 66% had 100% seizure 35 months No
(2006) were children max Mean reduction of generalized complication
Target: 2 target tonic-clonic seizures,
patients volume: 20–70% reduction of
posterior 0.28 cm3 partial seizures and
callosal progress in mental and
disconnection, physical development
1 patient
anterior
Pendl et al. 3 4 mm 160 Gy 100% significant 38 months 33% transient
(1999) collimator max reduction of severity and headache
Target: frequency of seizures
rostrum, genu,
and anterior
third of body
of the corpus
callosum
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Benign Lymphoid Disorders
Andrée-Anne Bernard
Contents 1 Lymphoid Hyperplasia:

1 Lymphoid Hyperplasia: Pseudotumor of Pseudotumor of the Orbit,
the Orbit, Castleman’s Disease 191 Castleman’s Disease
2 Thalassemia Extramedullary
Hematopoiesis with Spinal Cord Lymphoid hyperplasia is a polyclonal or oligo-
Compression 193 clonal lymphoid proliferation. It can be described
3 IgG4-Related Disease (Mikulicz as “reactive,” which is defined by a benign mor-
Syndrome) 194 phology and immunophenotype, or “atypical,”
4 Otitis Media 195 when the distinction from a lymphoma is more
difficult. Lymphoid hyperplasia may occur in any
References 196
part of the body but is often found in the orbit,
Waldeyer’s ring, and skin.
Lymphoid hyperplasia occurring in the orbit
has been termed orbital pseudotumor. It is gener-
ally unilateral, but synchronous bilateral disease
can occur in 15–36% of cases (Andrew et al.
2016). Once the diagnosis is confirmed, local
control can be reliably achieved with radiother-
apy at a dose of 20–30 Gy. Other modalities of
treatment include prednisone and rituximab.
Cutaneous lymphoid hyperplasia is classified
into four groups: nodular, pseudo-mycosis, intra-
vascular, and other (Mitteldorf and Kempf 2017).
The possible causes are varied and include der-
matitis, tattoos, viral infections, infection with
Borrelia burgdorferi, and drugs (including anti-
psychotics, antihypertensives, and antitumor
necrosis factor (TNF)-α agents) (Miguel et al.
2018). The primary intervention, when possible,
is to eliminate the causative agent. Other options
include surgical excision, intralesional or topical
A.-A. Bernard (*) corticosteroids, laser, and radiotherapy. Durable
Département de médecine spécialisée, Hôpital complete responses are described with doses of
régional de Rimouski, Rimouski, QC, Canada
e-mail: andree-anne.bernard.med@ssss.gouv.qc.ca 15–30 Gy (Joseph et al. 2016).

192 A.-A. Bernard
In the 1950s, Benjamin Castleman described an multicentric form can be associated with HHV-8
entity of angiofollicular lymph node hyperplasia or or POEMS (Polyneuropathy, Organomegaly,
giant follicular lymph node hyperplasia, which is Endocrinopathy, Multiple myeloma, and Skin
now known as Castleman’s disease. Other names changes) syndrome or can be idiopathic. Low
such as follicular lymphoreticuloma, angioma- doses of radiation have been used in adults to effect
tous lymphoid hamartoma, and giant benign lym- symptomatic relief of unresectable masses (Kyu
phoma have also been used. Castleman’s disease is Noh et al. 2013). It is essential, however, to con-
classified as either unicentric or multicentric. The firm that the underlying disorder is not lymphoma.
Lymphoid hyperplasia, pseudotumor of the orbit, Castleman’s disease

Total #
Author, year patients Sex/age Treatment Results Notes
Cutaneous lymphoid hyperplasia
Joseph et al. 1 M—21 30 Gy in 15 CR Follow-up of
(2016) fractions 28 months
Taylor et al. 1 F—63 20 Gy in 10 Recurrence 4 months Follow-up of
(2010) fractions after the first treatment 3 years
36 Gy in 18 Complete response after
fractions at second treatment
recurrence
Olson et al. 4 Ages: 1500 rad in 5 Complete regression in 8 months–7
(1985) 28–67 years. 1 fractions all cases. One marginal years’ follow-up
female and 3 recurrence
males spontaneously remitted
Pseudotumor of the orbit
Mokhtech 20 F—13, M—7 4.8–40 Gy CR—40% Median follow-up
et al. (2018) patients (typically 20 Gy in PR—35% of 8 years
(24 10) LC—63% at 5 years and
orbits) 53% at 10 years
Matthiesen 16 F—8, M—8 14–30 Gy, median Clinical Median follow-up
et al. (2011) patients dose of 20 Gy in response—87.5% of 16.5 months
(20 10 fractions CR—56.3%
orbits) PR—25%
Lanciano et al. 23 F—15; M—8 20 Gy/2weeks CR—87% for soft-tissue Median follow-up
(1990) patients Age: swelling of 41 months
(26 15–88 years 82% for proptosis, 78%
orbits) (median 55) for muscle dysfunction
75% for pain
Austin- 20 orbits Ages: 2000–3600 rad 15/20 complete No complication
Seymour et al. 25–80 years resolution
(1985) Mean 55 years
13 females and
7 males
Jereb et al. 5 Ages: 2000–2500 rad All with no evidence of
(1984) 23–76 years. 4 disease
females and 1
male
Sergott et al. 19 Ages: 1000–2000 rad 15 orbits responded 15 had failed
(1981) patients 23–83 years, 12 favorably. 6 orbits did previous steroids.
(21 females and 7 not respond Mean follow-up
orbits) males 25 months
Kennerdell 10 6 F; 4 M 25–30 Gy in All 10 had All with orbital
et al. (1979) Age 10 days to area of CR. Follow-up 6 lymphoid
46–79 years lesion months–5 years hyperplasia
Benign Lymphoid Disorders 193
(continued)
Total #
Castleman’s disease
Beckham et al. 6 F—6 36–59.4 Gy Local progression-free Follow-up of
(2020) Median age of survival—100% 3 years
42 years
Karaca et al. 1 15 years 45 Gy in 17 PR Follow-up of
(2014) F fractions 18 months
Kyu Noh et al. 4 F—4 36 to 50 Gy CR—75%
(2013) PR—25%
Neuhof and 5 F—3; M—2 40–45 Gy CR—40% Median
Debus (2006) Age: 2 patients had PR—33% Follow-up of
22–71 years partial resection Stable disease—20% 12 months
Chronowski 4 Age: 40 Gy in 20 CR—75%
et al. (2001) 24–51 years fractions or PR—25%
39.6 Gy in 22
fractions
Kim et al. 5 F—3; M—2 12–20 Gy/5– Type II (lymphocytic); Follow-up greater
(1987) Age: 15 days 2/2—CR than 5 years
14–71 years Type I (inflammatory);
1/2—CR 1/1—NR
Stokes et al. 1 45 years 39 Gy/22 fractions No evidence of disease Castleman’s
(1985) Male with 25 MeV at 5-year follow-up disease with
photons from T7 associated
to T12 vertebral
destruction
Marti et al. 1 73 years 12 Gy/10 fractions CR at 20-month
(1983) Male to cervical region follow-up
Weisenburger 1 51 years 27 Gy/15 fractions Dramatic response with Giant lymph node
et al. (1979) Female to unresectable complete resolution of hyperplasia with
mesenteric mass profound anemia. 2-year anemia
follow-up
2 Thalassemia Extramedullary 2015). On rare occasions, the extramedullary

Hematopoiesis with Spinal hematopoiesis can cause a spinal cord compres-
Cord Compression sion. There is no standard treatment, and options
include blood transfusions, hydroxyurea, sur-
Thalassemia is a genetic disorder associated with gery, and radiotherapy depending on the severity
a reduced rate of synthesis of one or more globin of presentation (Varlet et al. 2010). Since the
chains of the hemoglobin molecule and, thus, hematopoietic tissues are sensitive to radiation,
may cause anemia. Extramedullary hematopoie- doses as low as 10 Gy can achieve a satisfactory
sis is present in 15–20% of cases (Maazoun et al. response.
Total # of
Subahi et al. 1 Male 20 Gy in 10 fractions Significant
(2021) Age: 18 years improvement in
symptoms
Fontanesi 1 Male 30 Gy in 15 fractions at CR
et al. (2020) Age: 72 years two sites
(continued)
194 A.-A. Bernard
(continued)
Total # of
Ammar et al. 1 Male 30 Gy in 6 fractions CR Follow-up of
(2020) Age: 20 years 5 months
Fareed et al. 1 Male 20 Gy in 10 fractions PR on MRI
(2017) Age: 19 years Complete
neurological
response
Maazoun 7 M—5 , F—2 Surgery alone—1 CR—2 RT: 16 Gy in 8
et al. (2015) Age: 23–53 Hydroxyurea—3 PR—3 or 10 fractions
Hydroxyurea and RT—2 Relapse—2 (1 after
RT alone—1 RT)
Ruo Redda 1 Male 10 Gy in 5 fractions CR Fallow-up of
et al. (2014) Age: 35 years 45 months
Varlet et al. 43 M—32, F—11 Hypertransfusion—3 CR—85% Follow-up from
(2010) (review) Age: 9–45 years Hydroxyurea with or PR—10% 4 weeks to
(mean: without transfusion—5 Relapse—7.5% 15 years
27 years) Surgery—14
RT—11
Hydroxyurea and RT—4
Surgery and RT—4
Surgery, RT, and
hydroxyurea—2
Pistevou- 3 M—3 20 Gy in 10 fractions CR—3
Gompaki Age: 19, 34, and
et al. (1996) 42 years
Singhal et al. 35 M—26, F—8 Hypertransfusion—2 CR—32 Literature
(1992) Age: Surgery alone—4 PR—1 (surgery and review
14–55 years Surgery and RT)
hypertransfusion—1 NR—2 (surgery
Surgery and RT—11 alone)
RT and
hypertransfusion—1
RT alone—16
3 IgG4-Related Disease differentiated from Sjögren’s syndrome by the

(Mikulicz Syndrome) absence of anti-SS-A/SS-B antibodies and a high
ratio for serum IgG4/total IgG (Yamamoto et al.
Mikulicz syndrome is characterized by a bilateral 2006).
swelling of the lacrimal, parotid, and subman- Cases of Mikulicz syndrome treated by radio-
dibular glands. It has long been thought to be a therapy have been reported. That being said, glu-
subtype of Sjögren’s syndrome. However, since cocorticoids are the standard treatments. For
the 2000s, it is categorized as an IgG4-related cases that are refractory to glucocorticoids,
disease. Indeed, Mikulicz syndrome, or IgG4- rituximab is also an option (Carruthers et al.
related dacryoadenitis and sialoadenitis, can be 2015).
Total # of
Roos et al. 1 30 Gy in 15 Initial response with Radiotherapy was
(2019) recurrence 1 year used to treat what was
posttreatment thought to be
Kimura’s disease
Leban and 1 male age Treated with 250 rads × 4 Response to treatment Histopathology is
Stratigos 28 years fractions reviewed
(1974)
(continued)
Total # of
Jeleniewska 13 7.5–12 Gy skin dose over Durable response in all
(1970) 5–20 days patients
Schindel and 1 (bilateral Partial left parotidectomy Nodules on the right Pathology report:
Levie (1969) disease) with radiotherapy of parotid gland disappeared benign
1600 rads/9 days (200 Kv, completely lymphoepithelial
0.5 mm Cu, FSD 50 cm) to lesion
the right parotid
Radiotherapy, 1600 R, 1 yr.
later to the left parotid
gland for a recurrence
Hazel and 10 6–13 Gy fractionated Response in all but one
Bouchard patient (who stopped
(1964) treatment at 2.6 Gy)
Morgan and 18 Surgical excision alone (11) 16/16 no recurrence of
Castleman Age: or excision plus irradiation disease locally or spread to
(1953) 15–70 years (5) other organs (3 patients
2 patients received no died of apparently
treatment non-related causes)
Heaton and 1 Radiotherapy, 1200 R/6 Fx, Regression of the lesions.
Shannon to both parotids (200 Kv, Bilateral recurrences
(1948) 01.5 mm Cu plus 1 mm A1 1.5 years later were again
filtration) treated with radiotherapy,
resulting in rapid
subsidence of swelling
4 Otitis Media With long-term follow-up, secondary solid

tumors are now being reported, even following
Radium or strontium applications to the nasophar- low doses of radiation to small volumes. The
ynx for the treatment of bilateral serous otitis group from Washington County reported a rela-
media, conductive hearing loss, and “glue-ear” tive risk of benign and malignant tumors of
were commonly employed in the 1950s. 30.9 in a population who received radium treat-
Therapeutic response with normal hearing, normal ment of the nasopharynx for adenoid hypertro-
drums, and no subsequent otitis was common. The phy (Yeh et al. 2001). An increased risk of facial
mechanism of response was related to the ability of basal cellular carcinoma was also noted in a
radiation to reopen the eustachian tubes blocked by Dutch cohort (Ronckers 2002).
swollen lymphoid tissue, allowing drainage and Today, treatment with radiation for this
resolution to occur, as would a tympanostomy. The inflammatory process is of historical interest.
effect was not bactericidal (Berk and Hodes 1991).
Investigator,
year Cases Site, age Treatment Results Notes
Schultze 40 Eustachian 6 Gy in 6 fractions Significant Patients treated
et al. (2003) tubes, median improvement in 70% of 1980–1997
age of 58 years patients
Verduijn 2510 Nasopharynx Radium Rx 1200 mg/ No excess mortality Case-control study
et al. min noted, but a marginal with 20-year
(1989), Yeh excess in lymphatic follow-up
et al. (2001) malignancies noted in
exposed males
(p = 0.07)
(continued)
196 A.-A. Bernard
(continued)
Investigator,
year Cases Site, age Treatment Results Notes
Sofferman 1 Nasopharynx; 50 mg Crowe- 23 years later, found to Used for bilateral
and Heisse 31 years Burnam radium have adenoid cystic serous otitis media.
(1985) application 12.5 min carcinoma of the Not conclusive, but
to each side of nasopharynx likely is a radiation-
nasopharynx in 3 induced malignancy
treatments over
2 weeks (~4000 r
ranging to 320 r
1 mm from source)
Loeb (1979) 41 Nasopharynx; 1 “Crowe” applicator Of 28 patients with Patients had recurrent
to over 30 years 50 mg radium 12 min long-term follow up: 24 serous otitis,
to each side of had good results, 2 had conductive hearing
nasopharynx for 3 fair results, 2 had poor loss, and visible
treatments in 2 weeks results. No secondary lymphoid tissue in the
tumors nasopharynx.
Follow-up
15–30 years after
therapy
Bourdial 630 Rosenmüller “Crowe” applicator Complete
et al. (1970) fossa 50 mg radium resolution—72%
Treatment up to Improvement in
12 min depending on frequency and
age intensity—15%
Beck (1969) 663 Parapharyngeal Sr-90, 900–1600 r Average clinical
tube orifice improvement in 70% of
patients
Loch and 60 Nasopharynx Radon applicators Improvement of
Fischer symptoms in 97% of
(1952) patients
CR—52%
Fowler 88 Nasopharynx, 68 Radon capsule of 97% free from otitis
(1944) soldiers 75 mCi; 2 g min to
each side
Fisher et al. 100 Nasopharynx 50 mg radium Improvement of Follow up of
(1943) applicator; 2 g min to symptoms in 94% of 6–8 weeks
each side patients
Friedman 100 External 30–100 r Clinical cure in about Recurrence in about
and Hinkel auditory canal 70% of cases 8%
(1941) 4–75 years old
Beckham TH, Yang JC, Chau KW, Noy A, Yahalom J

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Pain Disorders
Christian Iorio-Morin,
Samuelle-Arianne Villeneuve,
Contents Pain is a debilitating symptom present in many

1 Trigeminal Neuralgia 199 diseases and has a significant impact on the qual-
ity of life. While radiation is widely used to treat
2 Glossopharyngeal Neuralgia 201
malignant pain through direct tumor irradiation,
3 Trigeminal Autonomic Cephalalgias 202 it has been shown to be effective in many benign
4 Celiac Pain 204 disorders as well. In most cases, radiosurgery is
5 Central Pain Procedures 205
used to treat a dysfunctional nerve or plexus,
although targets in the brain affecting pain per-
References 208 ception and integration pathways have also been
described.
This chapter reviews radiosurgery for pain
disorders, including trigeminal and glossopha-
ryngeal neuralgia, trigeminal autonomic cepha-
lalgias, and celiac pain. We will conclude by a
review of central pain interventions (hypophy-
sectomy and medial thalamotomy) used when
pain is centralized or diffuse or when the periph-
eral pain generator cannot be addressed.
1 Trigeminal Neuralgia
Trigeminal neuralgia (TN) is among the most

successful applications of radiation for the treat-
ment of non-oncological disorders. The disease is
C. Iorio-Morin · S.-A. Villeneuve · D. Mathieu characterized by short (<2 min) and severe elec-
Division of Neurosurgery, Department of Surgery, tric shock-like pain precipitated by innocuous
Université de Sherbrooke, Sherbrooke, QC, Canada
e-mail: christian.iorio-morin@usherbrooke.ca; stimuli in the trigeminal nerve distribution
samuelle.villeneuve@usherbrooke.ca; (Headache Classification Committee of the
david.mathieu@usherbrooke.ca International Headache Society (IHS) 2018). It
L. Masson-Côté (*) most frequently results from microvascular com-
Division of Radiation Oncology, Department of pression of the trigeminal nerve by an adjacent
Nuclear Medicine and Radiobiology, Université de artery or vein (classical TN). Secondary TN is
Sherbrooke, Sherbrooke, QC, Canada
e-mail: laurence.masson-cote@usherbrooke.ca most often caused by tumors (meningioma,

schwannoma) or multiple sclerosis. The thera- sive and uncomfortable, but usually have an
peutic effect of radiation on TN is thought to pri- immediate effect. For the majority of patients,
marily affect the myelin sheet around nerve however, radiosurgery provides an effective,
axons, preventing ectopic action potential gener- minimally invasive, and well-tolerated option. It
ation without inducing a conduction block that is the most frequently performed intervention for
would lead to complete nerve dysfunction (Devor TN in our practice.
et al. 2002; Régis et al. 2010). Radiation is typi- Table 1 presents the larger (>200 patients)
cally delivered on the cisternal segment of the published SRS studies for TN. An International
trigeminal nerve using single-fraction stereotac- Stereotactic Radiosurgery Society practice guide-
tic radiosurgery (SRS) techniques. line is also available and includes a meta-analysis
The decision to perform radiosurgery for TN of 6461 patients across 65 studies (Tuleasca et al.
should always be weighed against the other ther- 2018). Initial freedom from pain without medica-
apeutic options, which include medication, tion was achieved in 49–56% of patients after a
microvascular decompression, and nerve-mean of 15–78 days. Freedom from pain when
damaging percutaneous rhizotomies (e.g., bal- including patients still taking medication was
loon compression, glycerol injection, or achieved in 79–87% of patients. Recurrence was
radiofrequency thermocoagulation). Because it observed in 24–32% and occurred at a mean of
does not address the underlying cause of TN, 6–48 months after the initial treatment. Pain
radiosurgery is less effective and durable than relief was maintained at 10 years in 30–45%.
microvascular decompression. Pain relief is also Repeat radiosurgery has been reported and can be
achieved after a mean latency period of performed if trigeminal nerve function remains
15–78 days, making it less interesting in patients intact. The most frequent complication is hypoes-
with unremitting, severe episodes, as opposed to thesia in 22–29%, which can be bothersome in
percutaneous rhizotomies, which are more inva- 3–9% of patients (Tuleasca et al. 2018).
Table 1 Studies of >200 patients who underwent radiosurgery for trigeminal neuralgia
Total # Median
of maximal Complications/
Author, year patients Technical details dose Results Follow-up time comments
Mureb et al. 404 GK 80 Gy 92% pain Mean—32 months 24%
(2020) free hypoesthesia
42%
recurrence
Romanelli et al. 343 Cyberknife 75 Gy 92% pain Mean—15 months 6% hypoesthesia
(2019) free
(includes 24%
patients from recurrence at
other series 3 years
Romanelli et al.
(2017), Conti
et al. (2020))
Debono et al. 301 LINAC 90 Gy 91% pain Mean—55 months 26%
(2019) Retrogasserian free hypoesthesia
target 52%
recurrence at
10 years
Zhao et al. 247 GK 84– 88% pain Median—50 months 32%
(2018) 2 isocenters at 90 Gy free hypoesthesia
REZ 50%
recurrence at
50 months
Pain Disorders 201
Table 1 (continued)
Total # Median
Régis et al. 497 GK 85 Gy 92% pain Median—44 months 21%
(2016) 7.6 mm free hypoesthesia
(includes anterior to 34%
patients from REZ recurrence at
older series a mean of
Marshall et al. 24 months
(2012))
Taich et al. 263 GK 85 Gy 79% pain Median—24 months Hypoesthesia
(2016) 2–4 mm free Mean—21 months rate NR
anterior to 30%
REZ recurrence
Kotecha et al. 870 GK 86 Gy 86% pain Median—37 months 57%
(2016) at REZ free hypoesthesia
19% 1% anesthesia
recurrence dolorosa
Lucas et al. 446 GK 90 Gy 85% pain Median—21 months 42%
(2014) 2–4 mm free hypoesthesia
(includes anterior to 50%
patients from REZ recurrence
older series
Marshall et al.
(2012))
Young et al. 315 GK 90 Gy 86% pain Mean—69 months 33%
(2013) 2–4 mm free hypoesthesia
anterior to 14%
REZ recurrence
Verheul et al. 450 GK 80 Gy 75% pain Median—28 months 29%
(2010) at REZ free hypoesthesia
Recurrence 0.3%
NR deafferentation
pain
Kondziolka 503 GK 80 Gy 89% pain Median—24 months 11%
et al. (2010) 2–4 mm free hypoesthesia
(includes anterior to 43% 0.2%
patients from REZ recurrence at deafferentation
older series a mean of pain
Kondziolka 48 months
et al. (1998),
Maesawa et al.
(2001))
GK Gamma knife, NR not reported, REZ root entry zone
2 Glossopharyngeal Neuralgia pharyngeal branches of the vagus nerve

(Headache Classification Committee of the
Glossopharyngeal neuralgia (GN) is a cranial International Headache Society (IHS) 2018). As
nerve compression syndrome similar to trigemi- such, the pain attacks will involve the ear, base
nal neuralgia (TN) but affecting the glossopha- of the tongue, tonsillar fossa, and/or angle of the
ryngeal nerve and sometimes the auricular and jaw and can be associated with vasovagal shock.
Table 2 Series of >1 patients who underwent radiosurgery for glossopharyngeal neuralgia
Median
Author, Total # of maximal Complications/
year patients Technical details dose Results Follow-up time comments
Chai et al. 7 GK on 80– 100% Median—68 months 14%
(2021) glossopharyngeal 90 Gy significant after first and palatoglossal
meatus of the pain relief 45 months after hyperesthesia
jugular foramen 29% pain second
after MVD recurrence
Lara- 8 GK on 90 Gy 100% Median—7 years No adverse
Almunia glossopharyngeal significant event reported
et al. meatus of the pain relief
(2021) jugular foramen 38%
recurrence
Balossier 6 GK (second or third 85 Gy 83% Median—12 months 17% pharyngeal
et al. procedure) on significant hypoesthesia
(2020) glossopharyngeal pain relief after second GK
meatus of the All patients surgery
jugular foramen recurred
Borius 21 GK on cisternal 85 Gy 81% pain free Mean—5 years 4.8%
et al. segment 59% pain dysesthesia of
(2017) recurrence the edge of the
tongue
Pommier 9 GK on 90 Gy 89% Mean—46 months No adverse
et al. glossopharyngeal significant event reported
(2018) meatus of the pain relief
jugular foramen 44% pain
recurrence
Kano 22 GK 80 Gy 73% Median—45 months 9%
et al. significant hyperesthesia in
(2016) pain relief the palatoglossal
32% pain arch
recurrence
Xiong 3 GK on medial 80 Gy 100% pain Median—22 months No adverse
et al. cisternal segment free event reported
(2015) No pain
recurrence
Because it is 100 times rarer than TN, few series 3 Trigeminal Autonomic
are available to guide management. However, Cephalalgias
outcomes following radiosurgery appear similar
to those obtained with TN, with 73–100% of Trigeminal autonomic cephalalgias (TAC) are a
patients achieving significant pain relief at least group of unilateral headache disorders with
temporarily. No motor complication has been prominent cranial parasympathetic autonomic
reported so far. features ipsilateral to the pain. They are subdi-
Visualization of the glossopharyngeal nerve vided according to the duration of the attacks
on MRI can be unreliable, and its identification is and include cluster headaches (where attacks last
thus more challenging than for the trigeminal for 15–180 min), paroxysmal hemicrania
nerve. For this reason, the isocenter often targets (2–30 min), and short-lasting unilateral neuralgi-
the glossopharyngeal meatus or jugular foramen form headache attacks with conjunctival injec-
at the presumed location of the nerve. A stereo- tion and tearing (SUNCT) (1–600 s) (Headache
tactic CT is recommended to identify the fora- Classification Committee of the International
men and supplement MRI targeting (Table 2). Headache Society (IHS) 2018). These diseases
Pain Disorders 203
are thought to involve pathological activation of ing treatment, suggesting increased radiosensi-
a trigeminal-parasympathetic reflex mediated by tivity of the trigeminal nerve in this condition.
the sphenopalatine ganglion. As such, radiosur- The benefit of sphenopalatine irradiation in addi-
gery targeting the trigeminal nerve and some- tion to trigeminal nerve targeting remains to be
times also the sphenopalatine ganglion has been demonstrated. The data on SUNCT is even more
attempted. sparse, being limited to 5 papers reporting on 6
Series on cluster headaches have shown con- patients in total, of which 4 experienced signifi-
flicting results, with long-term improvement cant long-term improvement. As such, radiosur-
ranging from 0 to 100%. All studies report a high gery experience in these rare indications remains
rate (34–90%) of trigeminal dysfunction follow- anecdotal (Tables 3 and 4).
Table 3 Series of >1 patient who underwent radiosurgery for cluster headache
Total # Median
Kano et al. 17 GK on 80 Gy on 71% initial pain Median—34 months 50% facial
(2011) trigeminal each relief sensory
nerve and/or target 59% long-term dysfunction
sphenopalatine pain relief 18% hypesthesia
ganglion 12% paresthesia
without sensory
loss
6% paresthesia
with sensory
loss
McClelland 2 Repeat 75 Gy 0% long-term Mean—8 months 50% right facial
et al. (2007) procedure pain relief numbness
4 months
posttreatment
Donnet et al. 10 GK on 80 Gy 50% initial pain Mean—36 months 90% trigeminal
(2006) trigeminal relief disturbance
nerve 9 mm 30% long-term (60%
anterior to pain relief hypoesthesia,
REZ 30% paresthesia
with no
hypoesthesia,
20%
deafferentation
pain)
McClelland 10 GK on 75 Gy 60% good Mean—40 months 50% trigeminal
et al. (2006) trigeminal initial pain nerve
nerve relief dysfunction
0% long-term
pain relief
Ford et al. 6 GK on 70 Gy 100% 8–14 months 34%
(1998) trigeminal long-term dysesthesias
REZ improvement
(50% cured and
stopped
medication,
while 50%
improved, but
still have
residual pain)
Table 4 Series of radiosurgery for SUNCT

Total #
Author, of Median maximal Follow-up Complications/
year patients Technical details dose Results time comments
Zaed 1 GK on trigeminal 80 Gy on each Nearly pain free at 37 months No adverse
et al. nerve and target last follow-up event reported
(2020) sphenopalatine
ganglion
Tan et al. 1 Linac treatment of 90 Gy on Complete pain 16 months No adverse
(2013) trigeminal REZ and trigeminal REZ relief at last event reported
sphenopalatine 80 Gy on follow-up
ganglion sphenopalatine
Mathew 1 GK on trigeminal 80 Gy on each Complete pain 4 months No adverse
et al. REZ and target relief for 4 months event reported
(2012) sphenopalatine and occasional
ganglion brief pain episodes
thereafter
Effendi 1 GK on trigeminal 80 Gy on each Complete pain 39 months No adverse
et al. REZ and target relief at last event reported
(2011) sphenopalatine follow-up
ganglion
Black 2 GK on trigeminal 90 Gy Initial pain relief NR 50%
et al. nerve in 1 patient anesthesia
(2002) 0 long-term pain dolorosa
relief
4 Celiac Pain Although the neural structures themselves are

sometimes the sole target, in other cases, the
With the positive effects of radiation in trigemi- offending cancer is also treated, making the
nal neuralgia and the long history of celiac block mechanism of any clinical benefit uncertain. It is
in the management of abdominal pain, celiac too soon to know if such treatments will be inte-
plexus radiosurgery has recently been investi- grated in the standard management of abdominal
gated in the management of cancer pain. cancer pain.
Author, Total # of
year patients Technical details Time/dose Results Complications/comments
Hammer 21 pts (86% Dose-painting 19 pts: Decreased pain in Anterolateral aspect of the
et al. pancreatic VMAT technique 25 Gy/1fx all patients aorta from D12 to L2 used
(2018) cancer) RT to celiac 2 pts.: Median pain level as a surrogate marker for
plexus ± primary 45 Gy/5fx prior to RT = 6/10 the celiac plexus
tumor reduced to 2.3/10 Minimal toxicity limited to
at 3 weeks grade 1–2
Pain Disorders 205
5 Central Pain Procedures through downstream inhibition (Larkin et al.

2020). Medial thalamotomy (which is also per-
Pain results from the activation of a well-defined formed using stereotactic radiofrequency lesion-
neural network that starts with peripheral recep- ing in the operating room) is thought to interrupt
tors connected to the cerebral cortex through a thalamic projections to the posterior insular cor-
relay in the thalamus. When the source of pain in tex (where the characteristic of the pain is gener-
the periphery cannot be addressed (such as in ated) and to the anterior cingulate cortex (where
anesthesia dolorosa, poststroke pain, phantom the affective component of the pain is estab-
limb pain, trigeminal neuropathic pain, or diffuse lished) while sparing projections to the primary
cancer pain), pain pathways in the brain can be somatosensory cortex (where the location of the
targeted to provide relief. Two radiosurgical pain is determined). Pain therefore remains per-
interventions have been most studied: hypophy- ceived by the patient but is not as unpleasant
sectomy (mostly used for malignant pain) and (Franzini et al. 2021).
medial thalamotomy (mostly used for nonmalig- Both techniques have enjoyed fluctuating pop-
nant pain) (Roberts and Pouratian 2017). The ularity over the last 50 years, with their use
mechanism of action of hypophysectomy is not declining in the 2000s. They have consistently
understood (Hayashi et al. 2004); however, it is shown benefit in well-selected patients. Table 5
hypothesized that the hypothalamo-hypophyseal demonstrates all series of radiosurgical hypophy-
axis is affected, which may interrupt pain percep- sectomies for pain, and Table 6 pertains to radio-
tion and transmission signals from C fibers surgical thalamotomies for pain.
Table 5 Series of radiosurgical hypophysectomy for pain

Median
Total # of maximal Complications/
Hayashi 24 Target: Pituitary 140– 71% with Mean— Central
et al. (nonmalignant gland with the 50% 180 Gy initial 35 months hypothyroidism
(2007) pain) isodose covering the significant (33%)
lower stalk relief Transient diabetes
Localization: Bone 21% with insipidus (8%)
window CT, T1 final Worsening of
MRI, and T2 MRI significant prior paresthesia
relief (4%)
Kwon 7 (malignant Target: Junction 150– 100% with 2–13 months Transient diabetes
et al. pain) between pituitary 160 Gy initial insipidus due to
(2004) gland and stalk with significant pituitary
the 50% isodose relief hypofunction
covering the lower 100% with (14%)
stalk and upper part final
of the gland significant
Localization: T1 relief
and T2 MRI or 3D
fast spin-echo MRI
Delivery: One 8 mm
isocenter in 3
patients, two 4 mm
isocenters in 4
patients
(continued)
Table 5 (continued)
Median
Total # of maximal Complications/
Hayashi 9 (malignant Target: Junction 150– 100% with 1–24 months No adverse events
et al. pain) between pituitary 200 Gy initial For malignant
(2002) gland and stalk with significant pain
the 50% isodose relief
covering the lower 100% with
stalk and more than final
50% of the gland significant
Localization: Bone relief
window CT, T1
MRI, and T2 MRI
Delivery: One 8 mm
isocenter in 4
patients, two 4 mm
isocenters in 5
patients
Backlund 7 (malignant Target: anterior 200– 57% with 4–9 months Luteinizing
et al. pain) two-thirds of 250 Gy initial hormone
(1972) pituitary gland with significant deficiency (85%)
the 50% isodose relief Follicle-
kept within the sella 57% with stimulating
Localization: final hormone
conventional significant deficiency (43%)
plain-film relief Total urine
radiography gonadotropin
Delivery: 2–3 deficiency (57%)
isocenters using Urine osmolarity
3 × 5 mm or (43%)
3 × 7 mm cross- Protein-bound
sectional beams iodine deficiency
(71%)
Triiodothyronine
(29%)
Table 6 Series of radiosurgical thalamotomies for pain

Median
Franzini 8 Target: 130– 75% with Median—24 months No adverse
et al. (nonmalignant) posterior 140 Gy initial events
(2020) section of CL max dose significant Nonmalignant
Localization: relief
T1 and T2 62% with
MRI weighted final
images significant
correlated to relief
the stereotactic 12% pain
atlas recurrence
Delivery: 1
isocenter using
a 4 mm
collimator
5 patients
unilateral; 3
patients
bilateral
Pain Disorders 207
Table 6 (continued)
Median
Lovo 10 (1 Target: 130– 60% with Median—12 months No adverse
et al. malignant CM-Pfc 140 Gy initial events
(2019) pain; 9 Localization: significant
nonmalignant) T1 and T2 relief
MRI weighted 50% with
images final
correlated to significant
the stereotactic relief
atlas 10% with
Delivery: 1 pain
isocenter using recurrence
a 4 mm
collimator
Unilateral
Urgosik 30 Target: 140– 43% with Median—24 months No adverse
et al. (nonmalignant CM-Pfc 150 Gy initial events
(2018) pain) Localization: significant
T1 and T2 relief
MRI weighted 30% with
images final
correlated to significant
the stereotactic relief
atlas 13% of pain
Delivery: 1 recurrence
isocenter using
a 4 mm
collimator
Unilateral
Young 17 Target: 140– 65% with Mean—11 months Headache,
et al. (nonmalignant Intralaminar, 180 Gy initial nausea,
(1995) pain) mediodorsal, significant vomiting,
CM, and Pfc relief diplopia,
nuclei 65% with contralateral
Localization: final hemiparesis,
T1 MRI significant involuntary
correlated to relief movement of
the 24% pain contralateral
Schaltenbrand recurrence limbs (6%)
and Wahren Temporary
atlas worsening of
Delivery: 1 (1 prior
patient), 2 (17 contralateral
patients), or 3 hemiparesis
(2 patients) (6%)
isocenters
using a 4 mm
collimator
18 patients
unilateral; 2
bilateral
(continued)
Table 6 (continued)
Median
Steiner 49 (malignant Target: 140– 53% with NR Upward gaze
et al. pain) CM-Pfc 250 Gy initial weakness,
(1980) Localization: significant vertigo,
Conventional pain relief hemianesthesia
plain-film 8–37% with (4%)
radiography final Subdural
Delivery: 1 significant hematoma due
isocenter using relief to stereotactic
3 × 5 mm or 18% pain fixation device
3 × 7 mm recurrence (2%)
cross-sectional
beams
25 patients
unilateral; 24
patients
bilateral
CM-Pfc Centromedian-parafascicular complex, CL central lateral nucleus
Debono B, Lotterie JA, Sol JC et al (2019) Dedicated

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Psychiatric Disorders
M. Bret Schneider, Scott Soltys,

and John R. Adler Jr
Contents 1 Psychiatric Disorders:

1 Psychiatric Disorders: Overview 211
Overview
2 Obsessive-Compulsive Disorder (OCD) 212
Stereotactic radiosurgery has treated depression,
3 Major Depressive Disorder 213 anxiety, anorexia nervosa, and aggression in
4 Anorexia Nervosa 214 severely ill, treatment-refractory patients.
Noninvasive radiosurgical procedures were
5 Mixed Psychiatric Disorders 214
designed to emulate the results of invasive,
References 214 lesion-based procedures such as stereotactic cin-
gulotomy and anterior capsulotomy. Frequently,
target volumes are not specified, but may be
inferred from the collimator size (e.g., one 4 mm
isocenter corresponds with approximately
34 mm3) typically with specified dose delivered
to the 50% isodose line.
M. B. Schneider (*) Until recently, the psychosurgery literature
Department of Psychiatry and Behavioral Sciences,
typically lumped psychiatric disorders into heter-
Stanford University, Stanford, CA, USA
ogenous or otherwise poorly defined patient
Zap Surgical Systems, Inc., San Carlos, CA, USA
cohorts. Reported outcome measures were often
e-mail: bret@zapsurgical.com
arbitrary and cursory. In the absence of strong
S. Soltys
outcome metrics from rigorous baseline data and
Department of Radiation Oncology, Stanford
University School of Medicine, Stanford, CA, USA long-term follow-up, the therapeutic effect of an
intervention beyond generalized anergia could
J. R. Adler Jr
Zap Surgical Systems, Inc., San Carlos, CA, USA not be assumed.
Radiosurgical approaches to psychiatric dis-
Department of Neurosurgery, Stanford University
School of Medicine, Stanford, CA, USA ease require careful attention to the specific
e-mail: jra@stanford.edu diagnosis and subtype for case selection and

212 M. B. Schneider et al.
purposeful target selection. Treatment of psy- 2 Obsessive-Compulsive

chiatric disorders with ablative methods, includ- Disorder (OCD)
ing radiosurgery, should be undertaken only
when more conservative options have been Radiosurgical ablation of the anterior limb of the
exhausted. ventral internal capsule (ALIC) for the treatment
Chiefly because it is non-ablative, surgical of obsessive-compulsive disorder (OCD) is the
deep brain stimulation is growing as an alterna- only radiosurgical treatment for a psychiatric dis-
tive for treating severe refractory psychiatric disorder that has been studied to a reasonable degree.
orders, chiefly obsessive-compulsive disorder. A representative subset of publications are cited
Radiosurgery has the advantage of being nonin- below. The first radiosurgical capsulotomy was
vasive, and new radiosurgical techniques are performed by Leksell in the 1950s, and a series
being investigated that may enable nondestruc- followed at Karolinska. The procedure has been
tive neuromodulation (Schneider et al. 2021 subsequently refined as reviewed by (Miguel
Review). et al. 2019)
Total number of
Martínez- 10 Bilateral radiosurgical Response via Y-BOCS
Álvarez anterior capsulotomy in 7/10 patients
(2019) Dmax 120 Gy
Spatola 10 with refractory Two isocenters each 7/10 responders. 2 Low dose employed could
et al. (2018) OCD per side, Dmax 120 Gy nonresponders and 1 be related to low
targeted at partial responder. No incidence of AEs. Some
midputaminal point of “significant” AEs AEs were subjectively
ALIC reported, although reported by patients,
some subjectively including loss of interest
reported by patients (2), memory changes (2),
and weight gain (1)
Lopes et al. 16 Randomized Bilateral radiosurgical 5/8 response (≥35% Double blind maintained
(2014) with 8 receiving ventral capsulotomy YBOCS reduction) by for 12 months. First
SRS and 8 receiving with 2 4 mm isocenters 54 months; none in randomized, double-blind,
sham per sham group. 2/4 in sham-controlled study.
SRS. Crossover at target/Dmax = 180 Gy crossover group Retracted, revised, and
1 year for 4 that had responded by republished in 2015
previously received 12 months. Transient
sham cognitive changes and
development of 1
asymptomatic brain
cyst
Sheehan 5 Single 4 mm isocenter 4/5 with marked Retrospective assessment
et al. (2013) bilaterally, Dmax improvement by of patients at a median of
140–160 Gy YBOCS, 1/5 with 24 months
some improvement
(29% reduction). No
AEs reported
Kondziolka 3 Bilateral radiosurgical Follow-up at Numerical decreases and
et al. (2011) capsulotomy. Two 28–55 months found descriptive case reports
4 mm isocenters on to be improved (rather than categorical
each side, Dmax YBOCS scores from outcomes) emphasize
140–150 Gy 34 to 24, 39 to 8, and significant real-world
39 to 18. No AEs improvement
reported
Psychiatric Disorders 213
(continued)
Total number of
Taub et al. 5 Neuropsychological Improved expressive Subtle changes in
(2009) and cognitive testing on vocabulary, verbal cognitive abilities,
patients treated with reasoning, sustained improvement and
VC/VS capsulotomy attention, verbal worsening revealed by
learning, memory. formal
Decreased capacity to neuropsychological
divide attention testing
between stimuli in
three patients
Lopes et al. 5 Ventral capsule/ventral 3/5 subjects showed Brown University
(2009) striatum (“VC/VS”) 38% reduction or targeting method: 2
radiosurgical greater in YBOCS isocenters on ventral
capsulotomy score at 48 months. border of capsule. Name
AEs transient “VC/VS” reflects the
intent that ventral striatum
gray matter will also be
lesioned
Lippitz 10 from Karolinska Radiosurgical Right-sided lesion Supports hypothesis that
et al. (1999) SRS cohort capsulotomy as identified in all for this procedure,
compared with patients with good production of an
thermocapsulotomy outcome MRI-visible lesion may
be required for efficacy
Kihlstrom 14 from Karolinska Follow-up on bilateral Minimum of Dmax Spread of lesion to
(1997) cohort anterior capsule 110 Gy with a 4 mm caudate in 4/14 subjects.
Lesions produced by collimator was Lesion volume varied
gamma knife required to make a from 0 to 400 mm3
15–18 years prior white matter lesion on
T1 or T2 MRI
3 Major Depressive Disorder Ballantine et al. 1987), leading to radiosurgical

adaptation.
Severe, refractory depression has been treated
with some success by surgical cingulotomy (e.g.,
Total #
of
Martínez- 3 Bilateral radiosurgical “No side effects were observed.” No systematic side effect
Álvarez cingulotomy. Dmax 65% improvement in BDI after surveillance or evaluation.
(2019) 120 Gy via 2 adjacent 2 years. QOL improved by 70% More comprehensive
4 mm isocenters on at 2 years depression rating instruments
each side such as the Hamilton and the
MADRs are preferred for
depression studies
Kim and 4 in Radiosurgical Larger group including thermal Large target and associated
Lee (2008) SRS cingulotomy, using ablation cases had HAM prescribe dose are not readily
group 60–75 Gy to the 80% reduction from 38.5 at baseline comparable with most ablation
isodose line via to 10.5 at follow-up. “No studies. Retrospective study
10 mm collimator operative mortality.” Necrosis at with minimally specified
target zones as seen with outcomes
MRI. Edema and mass effect
214 M. B. Schneider et al.
4 Anorexia Nervosa cingulotomy (e.g., Ballantine et al. 1987), lead-

ing to radiosurgical adaptation.
Severe, refractory anorexia nervosa has been
treated with some success historically by surgical
Total #
Martínez- 5 Bilateral radiosurgical BMI increased by average Methodologically
Álvarez cingulotomy. 2 4 mm 40% within 6 months, QOL limited retrospective
(2019) isocenters on each side, Dmax improved by 30%. “No side
140–160 Gy effects”
5 Mixed Psychiatric Disorders behavioral disorders (particularly the propensity

for aggression) has driven attempts to find a sur-
Historically, extreme difficulty in managing gical solution.
some patients with intractable psychiatric and
Del 10 with variable compound Radiosurgical Positive Methodologically limited

Valle diagnoses including capsulotomy (6 cases) outcomes retrospective with no
et al. aggression, depression, and radiosurgical reported. Variable metrics and long-term
(2006) Asperger’s, schizophrenia, limbic leucotomy (4 adverse effects, assessment
OCD, anxiety cases) some enduring
Kondziolka D, Flickinger JC, Hudak R (2011) Results fol-

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Ballantine HT Jr, Bouckoms AJ, Thomas EK, Giriunas IE 68:28–32
(1987) Treatment of psychiatric illness by stereotactic Lippitz BE, Mindus P, Meyerson BA, Kihlstrom L,
cingulotomy. Biol Psychiatry 22(7):807–819. https:// Lindquist C (1999) Lesion topography and outcome
doi.org/10.1016/0006-3223(87)90080-1. PMID: after thermocapsulotomy or gamma knife capsulot-
3300791. omy for obsessive-compulsive disorder: relevance of
Del Valle R, De Anda S, Garnica R, Aguilar E, Pérez- the right hemisphere. Neurosurgery 44:452–458. [dis-
Pastenes M (2006) Psychiatric radiosurgery with cussion 458–460]
Gamma Knife (review) [Radiocirugía psiquiátrica con Lopes AC, Greenberg BD, Noren G, Canteras MM,
gamma knife]. Salud Mental 29(1):18–27. (Spanish) Busatto GF, de Mathis ME, Taub A, D’Alcante CC,
Kihlström L, Hindmarsh T, Lax I, Lippitz B, Mindus P, Hoexter MQ, Gouvea FS, Cecconi JP, Gentil AF, Ferrão
Lindquist C (1997) Radiosurgical lesions in the nor- YA, Fuentes D, de Castro CC, Leite CC, Salvajoli JV,
mal human brain 17 years after gamma knife capsu- Duran FL, Rasmussen S, Miguel EC (2009) Treatment
lotomy. Neurosurgery 41:396–402 of resistant obsessive-compulsive disorder with ven-
Kim MC, Lee TK (2008) Stereotactic lesioning for mental tral capsular/ventral striatal gamma capsulotomy:
illness. Acta Neurochir Suppl 101:39–43 a pilot prospective study. J Neuropsychiatry Clin
Neurosci 21:381–392
Psychiatric Disorders 215
Lopes AC, Greenberg BD, Canteras MM, Batistuzzo MC, update. Cureus 13(4):e14700. https://doi.org/10.7759/
Hoexter MQ, Gentil AF, Pereira CA, Joaquim MA, de cureus.14700. PMID: 33927960
Mathis ME, D’Alcante CC, Taub A, de Castro DG, Sheehan JP, Patterson G, Schlesinger D, Xu Z (2013)
Tokeshi L, Sampaio LA, Leite CC, Shavitt RG, Diniz Gamma Knife surgery anterior capsulotomy for
JB, Busatto G, Norén G, Rasmussen SA, Miguel EC severe and refractory obsessive-compulsive disorder.
(2014) Gamma ventral capsulotomy for obsessive- J Neurosurg 119:1112–1118
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Martínez-Álvarez R (2019) Radiosurgery for behavioral Vidal P, Richieri R, Régis J (2018) Results of Gamma
disorders. Prog Neurol Surg 34:289–297. https://doi. Knife anterior capsulotomy for refractory obsessive-
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Neuromodulation via focal radiation: radiomodulation
Reproduction
David Roberge
Contents 1 Abortion
1 Abortion 217
In the period between the two World Wars,
2 Anovulation/Sterility 218
radiotherapy was used to induce therapeutic
3 Ectopic Pregnancy 219 abortions in women at high risk of surgical com-
4 Male Therapeutic Castration 219 plications. As surgical abortions have become
4.1 Castration 220 safer, this indication is no longer current. There
5 Endometriosis 220 remain, however, pregnant patients with pelvic
cancers for which treatment delay until fetal
6 Female Therapeutic Castration 221
6.1 Ovarian Ablation for Breast Cancer 221 viability is judged inadvisable. For some of
these patients—notably when cervical dilatation
7 Uterine Bleeding 223
is impeded by the cancer—therapeutic radiation
8 Uterine Fibroids 224 for the cancer will also serve to terminate preg-
References 225 nancy (Morice et al. 2009). Data on the lethal
dose to the fetus is limited (and dependent on a
number of variables), but it appears similar to
that of total-body irradiation in adults, i.e.,
6–10 Gy (Hall 2000).
D. Roberge (*)
Department of Radiation Oncology,
Centre Hospitalier de l’Université de Montréal,
e-mail: david.roberge.med@ssss.gouv.qc.ca

218 D. Roberge
Total # of
Mayer et al. 200 360 cGy to the uterus 192 Average time to abortion was 35 days. Durable
(1936) (60% skin erythema dose) abortions amenorrhea was common above the age of 25.
12 patients had to have placenta removed
following abortion
Ganzoni and 33 Kilovoltage external 29 Authors attribute failure to cause abortion to
Widmer radiation of varied abortions technical issues with the technique and report
(1925) techniques, doses, and no failures when the uterus received
field sizes 250–800 cGy
domized data, and, in many cases, pregnancy

2 Anovulation/Sterility likely was achieved despite radiation. There are,
however, anecdotes of conception after long-
To use radiation therapy in an attempt to induce standing amenorrhea where it is tempting to attri-
ovulation and/or pregnancy is counterintuitive, bute a therapeutic effect to the treatment. With
and this was understood even as it was applied in advances in the diagnosis and management of
this indication in the first half of the twentieth infertility, there is no contemporary motivation to
century (Edeiken 1933). Both the ovaries and expose infertile women desirous of children to
pituitary were typically targeted. There is no ran- ionizing radiation.
Total #
of
Kaplan 800 Mean total dose to each 351/644 women with 543/566 normal healthy living
(1959) ovary ~65 cGy (range follow-up became children. 20 died at or after birth
~50–90 cGy). Mean total pregnant (from causes including
dose of 90 cGy to the automobile accidents) and 3 had
pituitary birth defects—abnormal number
of fingers in 2 and 1 with mental
retardation
Fullenlove 104 Pituitary and ovaries 46/88 women became
et al. (1956) treated weekly for 3 pregnant
fractions (single fields of
100 cGy in air each)
Ingalls et al. 80 Pituitary and ovaries 37/60 patients treated
(1955) for infertility conceived
12/20 treated for
amenorrhea menstruated
Ibrahim and 79 Pituitary (4–6 weekly Regular menses in 17/34 In all cases, hormones were
El-Shebini treatments of 100 cGy followed after pituitary combined with X-ray treatment
(1954) (surface dose to lateral treatment. Regular
fields)) alone or pituitary menses in 9/16 followed
and ovaries (3–4 ovarian after combined
fractions of 50 cGy treatment
(surface))
Asherman 100 55 treated to pituitary and Menses regulated in 13% iatrogenic menopause
(1952) ovaries 36% Both pregnancies and regulation
45 treated to pituitary Pregnancies in 33% of menses more common with
alone (600 r) ovarian irradiation, 43% vs. 28%
and 43% vs. 23%, respectively
Reproduction 219
Total #
of
Israel 124 105 cGy (d = 8 cm) in 3 71% cured of Cure defined as 1 year of regular
(1952) weekly fractions via amenorrhea cyclic menstruations (or
direct 140 kVp fields to pregnancy)
the ovaries and pituitary
Finkler 54 80 cGy in 4 fractions 13/28 resumed menses
(1949) over 2 weeks to the 20/54 conceived
ovaries and pituitary
Edeiken 56 4 fractions on days 40/56 resumed normal
(1933) 0–3–7–10 menstruation
7.5–12.5% skin erythema 11/33 conceived and
dose to the pituitary and delivered normal
ovaries children
treatments. Radiotherapy does not appear to have

3 Ectopic Pregnancy ever been a significant treatment modality for this
condition. The mention of the use of ionizing
Ectopic pregnancy is a potentially life-threatening radiation in the management of this condition is
condition with established surgical and medical solely of historical interest.
Total # of
Blumberg 4 Radium applied to the 4/4 pregnancies terminated with
(1947) abdominal wall uneventful recoveries
irradiated to as much as 6 Gy—even at 6 Gy, the

4 Male Therapeutic Castration azoospermia was typically transient (Rowley
et al. 1974).
Male castration using ionizing radiation has been X-ray castration for the purpose of hormone
used to induce sterility and/or decrease testoster- suppression has been described as a means of
one production. controlling behavior. There is anecdotal mention
As vasectomy has been available as a mini- in the management of “gender identity disorders”
mally invasive procedure since the late 1800s, the (Meyerowitz 2009). The main therapeutic inter-
use of radiation to limit procreation appears to est has been in the treatment of advanced prostate
have been used mainly in the context of geno- cancers. Although radiotherapy still had advo-
cide, eugenics, or what we would now consider cates for this indication in the 1940s, it is not a
unethical research. In these cases, radiotherapy reliable means of suppressing testosterone
may have been preferred for illegitimate reasons, production.
such as masking the sterilization from the subject Of historical interest, irradiation of the pitu-
or making it more socially palatable. As recently itary has been described in the unsuccessful treat-
as 1973, American prisoners had their testicles ment of male breast cancer (Treves 1949).
220 D. Roberge
4.1 Castration
Total #
Author, of
Faria 7 Therapeutic 1. No toxicity. 0/3 The regimens used were well tolerated but
et al. castration: Advanced maintaining castrate ineffective at producing castration at
(2015) prostate cancer: testosterone levels 11–36 months of follow-up
1. Single LHRH 2. 2/4 Grade I
agonist injection dermatitis. 0/4
followed by 17 Gy/2 maintaining castrate
2. Single LHRH testosterone levels
agonist injection
followed by 24 Gy/3
Munger 11 Nonmetastatic 8/11 patients alive at “A study of several cases treated by
(1941) prostate cancer 3–7 years testicular irradiation with resection seems to
post-resection and posttreatment indicate that slightly better results were
pelvic irradiation obtained than in those cases treated by
5 Gy to the testes (in resection and X-ray exclusive of the
addition to scattered testicular application”
dose from the pelvis)
5 Endometriosis number of women with endometriosis. Typically,

these treatments have aimed to reduce the symp-
Endometriosis is characterized by ectopic endo- tom burden. Radiation treatment of the infertility
metrial implants. The most common symptom is associated with endometriosis, although prac-
chronic pelvic pain. Bowel and bladder dysfunc- ticed, would seem counterintuitive. Considering
tion, abnormal uterine bleeding, or chronic current treatment alternatives, cases for which
fatigue can also occur. Infertility will commonly radiotherapy is considered are anecdotal (Nomiya
be seen in women with endometriosis and may in et al. 2012). Even today, there appears to be no
fact be the motivation for consultation. Treatment consensus as to whether to target only hormone
can be symptomatic, hormonal, or surgical. production (Haglund and Viswanathan 2008;
Historically, radiotherapy—either as a means of Thomas Jr. et al. 1997) or include the ectopic
castration or as an antiproliferative directed to the implants themselves (Nomiya et al. 2012).
endometrial implant—has been used in a large
Total # of
Brosset 101 100–150 cGy Of 84 cases retrospectively felt to Amenorrhea was induced in
(1957) directed to the have the correct diagnosis, 69 (82%) all patients menstruating
disease given once were objectively and subjectively prior to treatment; this was
(~40%) or repeated free of symptoms postradiation transient in 74%
A minority of
patients had
intentional radiation
castration
Schmitz 29 X-ray to unspecified 17 castrated by the treatment are 2 patients conceived
and Towne doses free of symptoms following treatment
(1948) 12 had temporary cessation of
menses, 1 required re-irradiation
Reproduction 221
6 Female Therapeutic In the management of fibroids, endometrio-

Castration sis, bleeding, or dysmenorrhea, ovarian ablation
has been used (Moore 1935). Often, this was
Pelvic radiation has been applied as a means of combined with pelvic radiation, the effects of
temporary contraception and sterilization but which are not easily separated from the effect of
more commonly as a hormonal treatment of breast reduced hormone production. These treatments
cancer or benign gynecological pathology. are addressed in other subheadings of this
As was realized early in its use, radiation is not chapter.
a reliable (or reasonable) means of temporary Since at least 1904, radiation has been used as
contraception—at risk of both not preventing the treatment of advanced breast cancer in the
pregnancy or causing permanent sterility. At pre- or perimenopausal patient (Bordier 1912).
higher doses, sterilization can be more predictable Although several randomized trials of the 1990s
but is accompanied by the ill effects of hormone and 2000s still treated LHRH agonists, surgical
suppression (“Although with their use there is no oophorectomy, and ovarian irradiation as inter-
mutilation, the final results produced by them are changeable means of achieving ovarian suppres-
similar to and as obnoxious as those of castra- sion (Zhang et al. 2017), there has been a sharp
tion.” (Babington 1928)). Although numerous decline in the use of ovarian irradiation. That
women were subjected to sterilization of this said, it appears to be an efficacious and cost-
nature, with or without their consent, the out- effective treatment that may have a role in special
comes are poorly documented. There is no routine circumstances, notably when resources are con-
contemporary indication for such a procedure. strained (Asiri et al. 2016).
6.1 Ovarian Ablation for Breast Cancer

Total #
of
Adjuvant 2144 1. Ovarian ablation or Overall, no effect of 11% of patients randomized
Breast Cancer suppression (1063 adding ovarian to ovarian ablation or
Trials patients—648 with radiation ablation or suppression suppression refused
Collaborative 16 Gy/4) to baseline tamoxifen treatment. In irradiated
Group (2007) 2. No ovarian ablation or and chemotherapy but women, ultrasound was
suppression (1081 patients) trend toward benefit in used to localize the ovaries
the ER+ subgroup
Ejlertsen et al. 762 1. Ovarian irradiation 15 Gy/5 No difference in Adjuvant treatment of
(2006) (317 patients) disease-free or overall hormone receptor-positive
2. CMF chemotherapy (445 survival breast cancer (tumor >5 cm
patients) or nodal positivity) in the
premenopausal patient.
Cessation of menses
achieved in 97% or
irradiated women
Thomson et al. 332 1. Ovarian ablation (167 No difference in Patients had stage II breast
(2002) patients—52 irradiated 15 Gy overall or disease-free cancer
in 5) survival (but strong
CMF chemotherapy (165 interaction with tumor
patients) ER content)
222 D. Roberge
Total #
of
Boccardo et al. 85 1. Surgical castration or No significant Ovarian irradiation was
(1994) irradiation differences (overall 15 Gy in 5 over 1 week
2. Goserelin survival 38 months 46% of patients in arms 1
3. Surgical castration or with irradiation/ and 3 were irradiated
irradiation + tamoxifen surgery vs. 36 months
4. Goserelin + tamoxifen with goserelin) but
trend (OS and PFS) in
favor of irradiation/
surgery
Nissen-Meyer 112 Prophylactic castration: Premenopausal Randomized prospective
(1967) Premenopausal poor-risk poor-risk patients: study showed no difference
patients: 1. Ovarian irradiation. between irradiation and
1. Ovarian irradiation 62% free of disease at surgical castration in
2. Oophorectomy 5 years. 71% crude poor-risk premenopausal
survival patients. Prophylactic
2. Oophorectomy 54% versus therapeutic castration
free of disease at showed benefit in
5 years. 68% crude postmenopausal stage II
survival patients
Kennedy and 177 1. Ovarian irradiation (123 Responders (objective Previous study by the same
Fortuny (1964) patients) remission): author showed no advantage
2. Bilateral oophorectomy (54 1. Irradiation: 56/123 to prophylactic versus
patients). Of the total number (45.5%) therapeutic castration
of patients, 177 were 2. Oophorectomy
premenopausal, 7 with vaginal 28/54 (50.1%)
smear estrogen activity within Mean duration
5 years of menopause 18 months, median
12 months
Block et al. 60 Therapeutic castration: Objective remission: Nonrandomized series with
(1960) 1. Irradiation (14 patients). 7/14 (50%) irradiation small numbers of patients
High-voltage irradiation. group, 12/46 (28.4%) which seems to favor
625–1100 r/10 days or less oophorectomy group irradiation castration
2. Oophorectomy (46 patients) Subjective remission:
8/14 (57.1%)
irradiation group,
16/46 (34.7%)
oophorectomy group
Treves (1957) 152 Prophylactic castration: 5-year survival: There is a statistical
1. Ovarian irradiation (84 54.4% controls difference between the
patients). Dose range of 8.1% irradiation controls and the surgically
300–1899 r, majority in the castration, 79.4% castrated at 5 years,
range of 1000–1499 r oophorectomy becoming more marked at
2. Oophorectomy (68 patients) Ten-year survival: 10 years. Irradiation
33.8% controls castrated patients benefitted
42.3% irradiation most at 10 years but not as
castration, 58.3% much as those who were
oophorectomy surgically castrated
Interval between
castration and
recurrence:
19.6 months in
irradiation series
25.3 months in
oophorectomy series
Reproduction 223
Total #
of
Smith and 101 Prophylactic castration: 5-year survival
Smith (1953) 1. Ovarian irradiation (41 (Patients with axillary
patients). 20 patients with metastases):
positive nodes 75% surgically
2. Surgical castration (60 castrateda
patients). 23 patients with 40% irradiation
positive nodes castrated, 31% not
castrateda
76% not castrateda
Douglas (1952) 184 1. Ovarian irradiation (175 1. Ovarian irradiation
patients) 700–800 r/1 week 36/175 (21%)
2. Surgical castration plus favorable response
testosterone (9 patients) 2. Surgical castration
1/9 slight response
Adair et al. 335 1. Irradiation (high-voltage 1. Irradiation
(1945) X-rays or intrauterine radium) castration: 15%
(304 patients) improved; 19%
2. Surgical castration (31 uncertain; 66% no
patients) improvement
2. Surgical castration:
13% improved; 23%
uncertain; 64% no
improvement
a
These values from authors, graphs
gia and metrorrhagia are often reported within a

7 Uterine Bleeding series of other benign gynecological conditions;
tens of thousands of women have likely been
A variety of causes of bleeding have been treated beyond those treated for fibroids (Roberts
addressed by radiotherapy. Treatment has been 1938). With such large number of patients treated,
delivered through intracavitary radium, telether- retrospective series have been able to document a
apy, or a combination of both modalities. subsequent increased risk of bladder cancer and
Although debated, much of the effect may be leukemia (Inskip et al. 1990a, b)—a factor in the
from hormone suppression—notably for peri- contemporary disinterest for this treatment
menopausal bleeding. Treatments for menorrha- modality.
Total #
of
Soiva and 214 Orthovoltage 4 fields 143/154 evaluable All had histological diagnosis of
Paavola (AP/PA to each ovary, 1 patients had success (0–2 cystic glandular hyperplasia
(1958) field per day) over episodes of bleeding
4 days, 600 cGy skin posttreatment)
dose
Stander 667 >85% X-ray (625 cGy to 95.8% effective 22% bleeding with fibroids, the
(1957) the ovaries) rest hyperplasia, polyps, or
<15% radium unexplained
(1200–2000 mg/h) All premenopausal
224 D. Roberge
Total #
of
Copeland 290 Radium dosed in relation 49–64% effective in age Lower doses in young patients
et al. to age (100–2400 mg/h) <30 less effective but 19/53 patients
(1957) 70% age 30–40 <30 years of age subsequently
>90% age 40–60 became pregnant (50%
miscarriages)
Czech 240 105 radium (𝛾) Immediate amenorrhea in
(1951) 60 X-ray 51/105, 26/60, and 46/75,
75 radium (𝛾 and β) overall failure in 3/240
Bock 206 3000–4000 mg/h radium 100% amenorrhea, 97%
(1944) immediate
Bach and 686 <1000 to >4000 mg/h 74% no further bleeding, Most common diagnoses were
Winkler radium (most 2% required a second menopausal bleeding (354) and
(1943) 2000–2500 mg/h) treatment (amenorrhea glandular hyperplasia (218)
was achieved in 100%)
Runge and 358 272 Radium 92% no bleeding Most common diagnoses were
Vöge (~2000 mg/h) post-radium (1.4% glandular hyperplasia (263) and
(1941) 86 X-ray (4-field treatment failure) endometritis (69)
300 cGy) 67% no further bleeding Treatment failure defined as
after X-ray (2.3% failure) more than 3 episodes of bleeding
Goecke 159 2000 mg/h in 87% 60% no further bleeding Most common diagnosis:
(1941) (2% failure) glandular hyperplasia (43%)
Windeyer 61 2400 mg/h radium 57 successful (no further Perimenopausal menorrhagia
(1938) bleeding or one period)
1 reduced bleeding
1 failure
2 lost to follow-up
Danforth 100 250–1200 mg/h radium 8 failures in patients
(1923) (based on patient age) receiving ≥1000 mg/h
Stacy 600 100–700 mg/h radium In patients <35 years old, One death 2 days after the
(1921) (depending on age) response to initial procedure
insertion in 56% and
hysterectomy in 7%
In patients >35 years old,
repeat treatment in 18%
and hysterectomy in 6%
8 Uterine Fibroids Most of the reported benefits were attributed to

the induction of menopause (Costolow 1941).
Radiation treatments of fibroids were adminis- Thus, although a theoretical role lingers in the
tered at a time when surgery was riskier, hor- minds of some (Nezhat et al. 2020), there is no
monal treatments were limited, embolization was standard role for radiation in the contemporary
not performed, and HiFU was not yet imagined. treatment of leiomyoma.
Reproduction 225
Total #
of
Crossen and 526 Gh Intrauterine radium 90% successful in In 96%, the symptom treated was
Crossen (1200–2400 mg/h) stopping myomatous bleeding
(1947) activity and associated
symptoms
Gauss (1943) 827 “320 Tr” Bleeding controlled in
99.4%
Costolow 986 61.5% radium and 29/986 required The report is of a 1927–1937
(1941) X-ray subsequent surgery subgroup (986 of the 1741 women
33% X-ray 65% of the 82 patients treated for fibroids in this practice).
5.5% radium with large tumors and Only 1 of 986 patients was treated
1–1.2 g radium/h and pressure symptoms were after menopause
400–500 cGy relieved
midplane by X-ray
Moore 244 “600–650 r per 15 sq. 95% “good results” Patients selected were between 35
(1935) cm field” in 2–4 daily 3% required subsequent and menopause. The treatment was
fractions using 4 fields surgery principally aimed at the ovaries
(200 kV X-rays)
Martindale 178 30–50% “unit skin 96.6% “cured”
(1929) dose” at 10 cm depth
to the ovaries
Zimmer IV 376 Fractionated X-ray 93.4% amenorrheic 3 women subsequently operated
(1927) “castration dose” for uterine sarcoma
Meyer et al. 2905 Varied techniques 86.3% durable
(1925) amenorrhea
62% shrinkage of the
fibroid
Hicks (1920) 98 1000–1800 mg/h 2% “absolute failures” Both failures in older women with
radium (in some cases, 14% not yet evaluable calcified fibroids
X-ray treatments 84% all symptoms
added) relieved
Kupferberg 325 600–7200 mg/h 97% well and
(1920) radium amenorrheic or
oligomenorrheic
Béclère 400 6–50 weekly X-ray Decrease in volume in all 12% had only temporary
(1919) treatments of 3–3½ patients, subsequent amenorrhea
Holzknecht units each surgery required in 1%
Kelly (1918) 210 1500 mg/h radium 70% with documented In 197/203 premenopausal
typical tumor reduction patients, menopause was induced
4% subsequent surgery
Asiri MA, Tunio MA, Abdulmoniem R (2016) Is

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Benign Tumors/Premalignant
Conditions
Houda Bahig and David Roberge
Contents 8 Pterygium of the Eye 257

8.1 Pterygium of the Eye 258
1 Adamantinoma 230
9 Hemangioma 263
2 Ameloblastoma 231
9.1 Head and Neck and Thoracic Hemangiomas 263
3 Adenomas of the Parotid (Salivary Gland 9.2 Hemangioma of Bone 267
Adenomas) 235 9.3 Liver Hemangiomas 271
3.1 Salivary Gland Adenomas 236 9.4 Cutaneous Hemangiomas 273
9.5 Hemangioma of the GI Tract 276
4 Angiofibroma of the Nasopharynx, 9.6 Hemangioma of the Urinary Tract 276
Juvenile Nasopharyngeal Angiofibroma 238 9.7 Hemangioma of the Joint 276
4.1 Angiofibroma (Nasopharynx) 239 9.8 Intracranial Angiomas 277
5 Choroid Plexus Papilloma 242 10 Inverted Papilloma 278
6 Pheochromocytoma and Extra-adrenal 10.1 Inverted Papilloma 279
Paraganglioma 243 11 Neurofibroma 280
6.1 Pheochromocytoma and Abdominal/
Thoracic Paraganglioma 244 12 Plasma Cell Granuloma/Inflammatory
6.2 Head and Neck Paraganglioma 245 Pseudotumor 281
7 Cystic Hygroma, Lymphangioma 255 13 Pineocytoma 282

7.1 Cystic Hygroma Radiotherapy and/or
References 283
Surgery 255
H. Bahig (*) · D. Roberge

Department of Radiation Oncology, Centre
Hospitalier de l’Université de Montréal,
e-mail: Houda.bahig.med@ssss.gouv.qc.ca;
david.roberge.med@ssss.gouv.qc.ca

Published Online: 12 May 2023
230 H. Bahig and D. Roberge
1 Adamantinoma pathological fracture (Qureshi et al. 2000). The

metastasis rate is reported to be around 10–20%,
Adamantinoma is a locally aggressive low-grade most commonly for the lungs (Jain et al. 2008;
bone tumor that is histologically similar to ame- Nouri et al. 2011; Papagelopoulos et al. 2007).
loblastoma (sometimes also called “jaw adaman- Limb-preserving surgery with en bloc tumor
tinoma”) (Van Rijn et al. 2006). The median resection with wide operative margins and limb
patient age at diagnosis is 30 years (Jain et al. reconstruction is the favored treatment approach
2008). The tumor typically occurs in the long and has been associated with local recurrence
bones, with a predominance for the midportion of rates between 10% and 20% (Keeney et al. 1989;
the tibia (85% of cases) but can also sometimes Qureshi et al. 2000; Bovee et al. 1998).
involve the fibula (Keeney et al. 1989; Baker Recurrence rates reach up to 30% in the context
et al. 1954), humerus (Huvos and Marcove 1975), of incomplete resection. Amputation is reserved
ulna (Sherman et al. 2003), femur (Makhson for the rare instances of local recurrence or if
et al. 2006), radius (Bourne et al. 1988), innomi- limb-preserving surgery is not feasible. These
nate bones (Lasda and Hughes Jr. 1979), ribs tumors have been described as both radioresistant
(Beppu et al. 1994), spine (Dini et al. 2006), and and chemoresistant. While some rare reports of
rarely bones of the hand and foot (Diepeveen the use of radiotherapy exist in the literature,
et al. 1960). Patients typically present with an there is no established role for radiotherapy in the
indolent growth over several years causing swell- treatment of adamantinoma. Palliative radiother-
ing with or without pain. Involvement of the ante- apy may prove useful in the treatment of hyper-
rior tibia can lead to a bowing deformity of the calcemia in metastatic disease (Lyons et al.
tibia, and up to 1 in 4 patients presents with a 1999).
Author, Total number

year of patients Treatment Results Notes
Quereshi 70 1. Limb salvage surgery Local recurrence rates Long bone adamantinoma,
et al. (59) were 8.6% at 5 years and series from 23 cancer centers
(2000) 2. Amputation (11) 18.6% at 10 years in Europe and North America
3. Adjuvant No radiation details provided
radiotherapy (2) Limb preservation rate was
4. Adjuvant radiation 84% (59 of 70), and the
and chemotherapy (1) survival rate was 87.2% at 10
years
Lyons 1 Palliative left Rapid improvement in Metastatic adamantinoma
et al. hemithorax 45 Gy via symptoms and with hypercalcemia
(1999) oblique field normalization of serum
arrangement using 6 and calcium levels
10 MV photons Asymptomatic 15 months
following radiotherapy
despite a gradual return of
elevated serum calcium
levels
Zand 1 Radiotherapy. 6200 r/42 At 2.5-year follow-up, Adamantinoma of the
et al. days, Co60 X-rays showed the lesion humerus in a 7-year-old boy
(1972) to be healed with no
evidence of recurrence.
No recurrence at 9 years.
At 8.5 years, right
humerus was 2 in. shorter
than the left humerus
Benign Tumors/Premalignant Conditions 231
Author, Total number

year of patients Treatment Results Notes
Moon 61 1. Irradiation only (1) 1. 1/1 recurred All were cases of
(1965) 2. Local excision with 2. 2 recurrences: adamantinoma of the
or without graft (24) 19 well, 0–10 years appendicular skeleton.
3. Amputation (36) 5 died, 0–10 years Review of reported cases of
3. 1 recurrence: adamantinoma of the
25 well, 0–10 years appendicular skeleton plus ten
11 died, 0–10 years new cases reported by the
author
2 Ameloblastoma cally progress slowly, but are locally invasive,

tend to recur, and, when uncontrolled, can cause
Ameloblastoma is a benign, slow-growing odon- significant morbidity and even death (Zwahlen
togenic epithelial tumor that accounts for approxi- and Gratz 2002; Chen et al. 2006a; Gortzak et al.
mately 10% of all tumors of the mandible and 2006). The reported rate of metastases from ame-
maxilla (Becelli et al. 2002; Buchner et al. 2006; loblastoma is approximately 2% (Ladeinde et al.
Fernandes et al. 2005a). The median age at 2006; Kumamoto and Ooya 2006).
presentation is 35 years (Reichart et al. 1995). Up The preferred treatment is wide local excision
to 80% arise in the mandible, usually in the molar- with 1–1.5 cm bony margins yielding local con-
ramus region (Becelli et al. 2002; Fernandes et al. trol of 90% (McClary et al. 2016; Becelli et al.
2005a; Reichart et al. 1995; Zemann et al. 2007; 2002; Carlson and Marx 2006; Zwahlen and
Ladeinde et al. 2006), with almost all remaining Gratz 2002; Ueno et al. 1989; Vayvada et al.
cases occurring in the maxilla (Amzerin et al. 2006; Chana et al. 2004). Depending on the loca-
2011). Presenting symptoms include slow-grow- tion and the extent of the lesion, surgery may
ing submucosal mass, loose teeth, malocclusion, entail marginal mandibulectomy, segmental man-
paresthesia, or pain (Becelli et al. 2002; Reichart dibulectomy, or partial maxillectomy (Zwahlen
et al. 1995). However, one-third of ameloblas- and Gratz 2002; Vayvada et al. 2006; Chana et al.
toma presents incidentally on routine dental 2004; Mendenhall et al. 2007). Conservative sur-
radiographic X-ray (Becelli et al. 2002). gical approaches such as enucleation or curettage
Ameloblastomas are classified as central multi- are associated with high recurrence rates reach-
cystic/solid (92%), central unicystic (6%), or ing up to 65% (Lau and Samman 2006; Ueno
peripheral (2%) (Reichart et al. 1995; Carlson and et al. 1989; Muller and Slootweg 1985; Nakamura
Marx 2006). Central ameloblastomas arise within et al. 2002; Chapelle et al. 2004). Postoperative
the jaw, while peripheral ameloblastoma presents radiotherapy (PORT) has been used in a limited
as a sessile or pedunculated base arising in the number of patients with microscopic or gross
gingiva without involvement of the underlying residual disease who are not amenable to re-
bone (Buchner et al. 2006; Fernandes et al. 2005a; resection. Definitive radiation has been reported
Carlson and Marx 2006; LeCorn et al. 2006). in rare patients felt to be poor surgical candidates
Multicystic/solid ameloblastomas are more (Atkinson et al. 1984; Kennedy et al. 2016;
aggressive and have a higher likelihood of recur- Miyamoto et al. 1991). The dose/fractionation
rence after surgery compared to unicystic and schedules have ranged from 45 to 66 Gy for
peripheral ameloblastomas (LeCorn et al. 2006; microscopic residual disease to 70 Gy for macro-
Lau and Samman 2006). Ameloblastomas typi- scopic disease, in 1.8–2 Gy per fraction.
Total
number
of
Petrovic 30 1. All had definitive 1. 5 recurrences (3 local, Ameloblastoma of the mandible
et al. (2018) surgery, 5 had positive 1 locoregional, 1 (15) or maxilla (15)
margins distant)
2. 2 patients with positive 2. Free of recurrence at
margins had PORT 9 and 10 years
3. 1 patient with 3. Free of recurrence for
locoregional recurrence 7 years and died of
had salvage surgery, other causes
followed by PORT 4. Alive with disease at
(6300 cGy) 8-year follow-up
4. 1 patient with initial
positive margin who
recurred had local
excision followed by
PORT (5580 cGy)
Kennedy 6 3 patients with Local control 67% (4 of 2 mandibular lesions, 4
et al. (2016) ameloblastoma and 3 6 patients) maxillary lesions
patients with ameloblastic Median observed follow-up
carcinoma treated with: time of 7.8 years
1. RT alone (2)
2. Surgery + PORT (4)
Median radiation dose was
66.2 Gy (range
63–74.4 Gy)
Madhup 1 Radical RT No recurrence at 2 years Giant inoperable tumor
et al. (2006) 60 Gy/30, parallel opposed invading the oral cavity and
lateral fields infratemporal fossa
Pinsolle 41 17: local recurrences after 2/41 died of progressive Radiotherapy to be used in
et al. (1995) curettage (14) or resection disease selected case after surgery, in
(3) the context of multiple
7 with 2 or more recurrences
recurrences
8: adjuvant RT to 50 Gy
Ueda and 1 Co60 radiation, 7080 r/80 Excellent clinical and Advanced disease involving
Kaneda days, and intra-arterial radiographic response paranasal sinuses responded to
(1991) bleomycin (85 mg/m2) with no recurrence at therapy. Tumor was not
10-year follow-up radioresistant or chemoresistant
Miyamoto 1 Radiotherapy, 54 Gy/30 fx Dramatic reduction in Patient was first treated with 11
et al. (1991) radiographic and clinical resections and with
tumor, with no disease at cyclophosphamide,
8-year follow-up methotrexate, and 5-FU without
resolution, and then with
adriamycin and bleomycin
without response. Good review
of the literature and discussion
of treatment
Total
number
of
Atkinson 10 7: radiation therapy alone; 6 responded, 1 recurred Authors recommend 45 Gy/4
et al. (1984) 3: radiation therapy and and was salvaged weeks, including treatment to
surgery surgically the entire hemimandible in
All 3 controlled mandibular lesions. Authors
conclude that tumor is not
radioresistant
Chandhuri 3 1. Local excision. 1. Recurrences 3 years All were cases of
(1975) Recurrence treated with later at a margin of ameloblastoma of the maxilla
partial excision of the original excision
maxilla (1) 2. No recurrence
2. Excision followed by 3. Almost complete
radiotherapy, 6000 r/21 resolution 6 months
days (1) after treatment
3. Radiotherapy, 4500 r/20
days (1)
Hartman 15 1. Enucleation (4) 1. 4/4 recurrences All were cases of granular cell
(1974) 2. Curettage (4) 2. 4/4 recurrences ameloblastoma of the mandible
3. En bloc excision (3) 3. 1/3 recurrences
4. Partial resection (2) 4. 0/2 recurrences
5. External irradiation (2) 5. 2/2 recurrences
Sehdev et al. 92 Mandible (72): Recurrences EBRT dose and fractionation
(1974) 1. Radiotherapy (9) 1. 9/9 (100%) not stated
2. Curettage (32) 2. 29/32 (90%) Radiotherapy did not adversely
3. Resection (31) 3. 5/31 (22%) affect prognosis after
Maxilla (20): 4. 2/2 (100%) subsequent resection. Distant
4. Radiotherapy (2) 5. 11/11 (100%) metastases occurred in 7
5. Curettage (11) 6. 0/5 patients
6. Resection (7)
Shaw and 3 1. Second recurrence 1. Patient was free of All were cases of
Katsikas following surgical disease 9 years later ameloblastoma of the maxilla
(1973) excision was treated 2. Good local
with radiotherapy, improvement. Patient
6000 r total dose, Co60 died 1.5 months later
(1) of unknown but
2. Radiotherapy, 5048 r/36 probably unrelated
days, Co60 (1) causes
3. Radiotherapy, 6250 r 3. Fair response to
total tumor dose, Co60. radiotherapy, but still
This was followed by some slight swelling.
surgical excision of Recurrence 7.5 years
residual tumor. later. This was treated
Recurrence treated by surgical excision.
surgically (1) No further recurrence
at 15-month
follow-up
Total
number
of
Pandya and 74 Primary cases: Recurrences: Authors state that radiation
Stuteville Mandibular lesions (40): 1. 1/4 (25%) alone does not significantly
(1972) 1. Enucleation with 2. 1/5 (20%) 5/39 affect this tumor, but it may
cauterization (4) (12.8%) have a place in conjunction
2. Intraoral local excision 3. 3/30 (10%) with surgery in the management
(5) 4. 1/1 of selected cases
3. Primary oral resections 5. 0/10
and bone grafts (30) 6. 2/23 (9%)
4. Palliative resection (1)
Maxillary lesions (10):
5. Maxillectomy.
Radiation was used as
an adjunct to surgery in
three patients, all of
whom responded to the
radiotherapy
Secondary cases (23):
6. Wide extraoral
segmental resection
plus bone graft
Sugimura 1 Mandibular ostectomy Patient lost to follow-up Malignant ameloblastoma of
et al. (1969) followed by chemotherapy until 3 years later. At that the mandible
(cyclophosphamide) and time, metastases to the
radiotherapy, 3900 r/15 lumbar vertebra were
days noted. Initially, these
responded to Co60
radiotherapy. Patient died
7 years after the onset of
primary lesion
Shatkin and 24 Primary cases: Recurrences: All were cases of
Hoffmeister 1. Curettage (13) 1. 11/13 (86%). Four ameloblastoma of the mandible
(1965) 2. Radiotherapy (2) later died of tumor or maxilla, the mandible being
3. En bloc excision (7) 2. 2/2 (100%). One later the more common site
died of tumor
3. 1/7 (14%)
Goldwyn 32 Primary cases: 1. 8/13 recurred (two Ameloblastoma of the mandible
et al. (1963) 1. Local excision (14) died from disease). (27)
2. Wide resection (3) One patient lost to Ameloblastoma of the maxilla
3. Palliative irradiation follow-up (3)
4. Local excision plus 2. 0/3 recurred
irradiation (1) 3. 1/1 recurred and died
Secondary cases: from disease
5. Local excision (4) 4. 1/1 recurred and died
6. Wide resection (9) from disease
7. Palliative irradiation (1) 5. 4/4 recurred
6. 0/7 recurred. Two
patients lost to
follow-up
7. 1/1 recurred and died
from disease
Hair (1963) 1 Radiotherapy, 3750 r/45 External swelling Ameloblastoma of the maxilla
days gradually diminished.
X-rays showed
recalcification
Total
number
of
Small and 211 1. Local excision or Recurrences: Statistical survey of the
Waldron curettage, including 1. 89/193 (46%) literature. Only cases of
(1955) chemical cautery or 2. 13/18 (72%) ameloblastoma of the maxilla
irradiation in some and mandible were included
cases
2. Irradiation alone (18)
3 Adenomas of the Parotid 2002; Myssiorek et al. 1990; Leverstein et al.

(Salivary Gland Adenomas) 1997). Enucleations are associated with high
rates of local recurrence ranging from 20% to
Pleomorphic adenoma is the most common neo- 45% (Glas et al. 2001; Donovan and Conley
plasm of the parotid gland. The median age at 1984). The role of postoperative radiation ther-
first occurrence is between 30 and 40 years apy in the management of recurrent pleomorphic
(Malard et al. 2013; Phillips and Olsen 1995). adenoma is controversial (Dawson 1989;
Recurrent pleomorphic adenoma, typically pre- Friedrich et al. 2005; Liu et al. 1995). Adjuvant
senting 10 years after the first surgery, is a chal- radiotherapy aims at improving local control
lenging entity. Although a local recurrence can (avoiding or delaying recurrence) and limiting
almost always be treated with repeat surgery, the repeated or morbid surgery associated with
rate of additional recurrence after a first recur- potential facial nerve damage (Becelli et al.
rence is as high as 50% (Stevens and Hobsley 2012). Patients with higher risk of recurrence
1982), and repeat surgeries are associated with include those with gross residual disease, close or
high risk of morbidity, notably facial nerve dam- positive margins, multifocal recurrence, perineu-
age (Phillips and Olsen 1995; Maran et al. 1984; ral invasion, or rupture of the capsule resulting in
O’Dwyer et al. 1986). In addition, the potential tumor spillage (Mendenhall et al. 2008; Park
for malignant transformation to carcinoma ex et al. 2012; Witt et al. 2015; Patel et al. 2014). On
pleomorphic adenoma after repeated recurrences the other hand, there is concern regarding the
has been reported to be as high as 9% (Phillips possibility of developing radiation-induced
and Olsen 1995; Zbaren et al. 2005; Olsen and malignancies in young patients (Larson 2001).
Lewis 2001). Any recommendation for postoperative radio-
The current standard of care for treatment of therapy should be the result of a multidisciplinary
pleomorphic adenoma is surgical resection, con- discussion (Bradley 2018). Dose is typically
sisting of superficial or total parotidectomy. 60–66 Gy in 30–33 fractions, based on margin
These surgeries are associated with local control status in the adjuvant setting, whereas a dose of
rates exceeding 95% (Stevens and Hobsley 1982; 70 Gy is typically prescribed for macroscopic
Malard et al. 2021; O’Brien 2003; Alves et al. disease (Malard et al. 2021).
3.1 Salivary Gland Adenomas
Author, year Total cases Site Treatment Results Comments

Aro et al. 47 Parotid or All had surgery for 14 patients (30%) 6% developed
(2019) submandibular first recurrence had a second carcinoma ex
gland Adjuvant RT (60 Gy) recurrence, including pleomorphic
in 3 patients after first 1 patient who had adenoma
recurrence been treated with
adjuvant RT
Abu- 22 Parotid 22 patients were No evidence of
Ghanem et operated disease progression
al. (2016) 9 patients had adjuvant or recurrence in 9
RT patients with
adjuvant RT
Patel et al. 21 Parotid with Median dose 57.6 Gy 19/21 patients (90%) Median follow-up
(2014) close or (range 55.8–69.96) had locoregional of 92 months
positive using 1.8–2.12 Gy/ control
margins fraction Actuarial survival
rate was 100%
Malard et 32 Recurrent 31% had 2 or more RT was not Most significant
al. (2013) pleomorphic surgical resections and associated with a risk factor for
adenoma of external adjuvant RT decrease in secondary
parotid recurrence recurrence:
presence of
multifocal tumor
9% progressed to
carcinoma ex
pleomorphic
adenoma
Wallace et 25 – RT alone (2 patients) 5-, 10-, and 15-year
al. (2013) or combined with overall local control
surgery (23 patients) rates were 76%,
76%, and 68%,
respectively
Robertson 190 Parotid 78/190 patients had a Recurrences
et al. primary incomplete occurred in 11/53 in
(2014) excision those observed and
25/78 received in 1/25 of those who
postoperative received
radiotherapy and 53 radiotherapy
were observed
Chen et al. 34 Recurrent EBRT 5000 cGy 20-year actuarial One patient
(2006b) pleomorphic (range, local control rate: developed a second
adenoma of the 4500–6000 cGy) 94% malignancy at 14
parotid years.
Radiation was
delivered for a first,
second, third,
fourth, fifth, and
sixth local
recurrence in 24%,
21%, 24%, 24%,
6%, and 3% of
patients

Hodge et 17 First diagnosisRT alone (2) 5- and 10-year
al. (2005) (7) Surgery + adjuvant RT overall local control
Recurrence (15) rates were 69% and
(10) Median dose of 65 Gy 61%
Parotid (12) (56.6–70 Gy) in
Parapharyngeal 1.8 Gy/fraction
space (2) 3 patients had
Nasopharynx twice-daily RT to a
(1) median dose of
Hard palate (2)74.4 Gy (62.9–74.4) in
1.2 Gy/fraction
Douglas et 16 Major salivary Median dose 18.9 10-year OS 79% 15-year risk of
al. (2001) glands neutron Gy (1.7 15-year LRC 85% non-audiologic
neutron Gy, 3 times a 15-year LRC 76% grade III/IV
week to 1.1 neutron with gross residual complications was
Gy, 4 times a week) disease vs. 100% 21%
with microscopic No facial nerve
disease injuries as a direct
consequence of
neutron RT
Renehan et 114 Recurrent Surgery alone (63) Second recurrence Median follow-up
al. (1996) pleomorphic Surgery + adjuvant RT rate: 15% (17/114) 14 years
adenoma of the (51) Multinodular 15% incidence of
parotid recurrence: permanent facial
Local recurrence at nerve injury
15 year 43% in
surgery group versus
4% in surgery + RT;
p = 0.008
Uninodular
recurrence:
Local recurrence at
15 year 15% in
surgery group versus
15% in
surgery + RT;
p = 0.9
Buchholz 6 – Fast neutrons, poor 100% local control Low facial nerve
et al. prognostic group. 52 months risk
(1992) Average had 3 surgical
procedures
Barton et 187 – 60 Gy cesium or Complex and mixed Surgery with spill
al. (1992) radium brachytherapy or residual should
until 1976 have X-ray
EBRT 50 Gy in 15–16
fractions over 20 days
Ravasz et 62 – 50 Gy post-op, 62/62 NED surgery
al. (1990) 20–25 Gy boost and post-op surgery
inoperable for recurrence
15/16 NED
18/20 controlled
Dawson 29 – Radium needle 18/20 controlled
(1989) 6000 R/6 days
5000–5500 cGy/20 fxs

Watkin and 65 Parotid gland Radiotherapy after a 44% of irradiated All recurrent
Hobsley 17 given local excision patients developed pleomorphic
(1986) radiotherapy (primary XRT), or local recurrence adenomas of the
following later within the first 5 parotid gland
recurrence (secondary years, not different 2/17 irradiated
XRT) 4500–6000 cGy from the 50% patients developed
(2 patients recurrence rate malignant
brachytherapy) among those who transformation of
did not undergo their tumors
postoperative Nonrandomized
radiotherapy study
Dawson 311 Parotid gland Surgery (local 1–1.5% recurrence All primary
and Orr excision) and rate at 0–5 and 5–10 pleomorphic
(1985) irradiation 5500– years (benign adenomas of the
6000 cGy via radium recurrence), 8% salivary glands.
needle implant or cumulative risk of Malignant
4 meV linear recurrence at 20 transformation
accelerator years (mostly occurs as a late
malignant tumors) event
Armitstead 76 Parotid gland Extracapsular 1/76 recurred with a All primary
et al. enucleation and malignant tumor pleomorphic
(1979) irradiation Co-60, adenomas of the
linear accelerator parotid gland.
4800 r/3 weeks Median follow-up
is not provided
4 Angiofibroma early stages and craniofacial approaches usually

of the Nasopharynx, used in more advanced disease (Leong 2013;
Juvenile Nasopharyngeal Moulin et al. 1995). Presurgical embolization
Angiofibroma reduces perioperative bleeding and facilitates
surgical access (Moulin et al. 1995). Radiation
Juvenile nasopharyngeal angiofibroma (JNA) is a therapy is an alternative option for unresectable
rare, highly vascular, benign tumor characterized disease and in cases of residual disease after sur-
by aggressive local growth (Martin et al. 1948; gery. In addition, surgery is associated with high
Bales et al. 2002). It is typically seen in young teen- morbidity and mortality in JNA presenting intra-
age males, with the median age at diagnosis being cranial extension; although controversial, radio-
15 years (Roger et al. 2002). The internal maxillary therapy is an attractive alternative modality in
artery and the ascending pharyngeal artery are the such circumstances. However, the risks of recur-
first and second most common vascular origin of rence should be carefully weighed against the
JNA. Intracranial involvement is seen in 10–40% long-term risks of radiotherapy in these young
of cases. Patients typically present with a history of patients (Lee et al. 2002). Cure rates of 80–90%
progressive nasal obstruction and recurrent epi- have been reported for both treatment modalities
staxis. Physical examination usually reveals a pink (Leong 2013; Jafek et al. 1979; Cummings et al.
or blue nodular mass in the roof of the nasopharynx 1984a). Radiotherapy doses used in the literature
(Roger et al. 2002; Lee et al. 2002). vary between 30 and 46 Gy in 3–5 weeks, using
Surgical excision is the treatment of choice, standard daily fractionation. Tumors typically
with transnasal endoscopic resection favored in regress slowly over 2–3 years after radiotherapy
(Economou et al. 1988).
4.1 Angiofibroma (Nasopharynx)

Total number
Author, year of patients Treatment Results Comments
Mallick et al. 31 Median radiation dose: Median PFS not RT was used for refractory,
(2015) 30 Gy (range: 30–45 Gy) reached. PFS rates at 3 residual, or unresectable
and 10 years were 92% disease. Median follow-up:
and 71% 36 months. 1 patient
developed squamous cell
carcinoma of the nasal ale
15 years after radiation
Amdur et al. 24 12 pts: 30–32 Gy/22 fx Dose-response for Median follow-up 18 years
(2011) 12 pts: 35–36 Gy/20 fx tumor control Authors recommend
RT to primary site alone 77% with 30–32 Gy vs. 36 Gy/20 fx
91% with 35–36 Gy
Chakraborty 8 Median dose 39.6 Gy 2 year LC: 88% All had inoperable stage
et al. (2011) (30–46 Gy) 1 patient died 1 month IIIB disease with
7 patients treated with after radiotherapy intracranial or intraorbital
IMRT secondary to massive extension
epistaxis Median follow-up: 17
7 patients had months
progressive resolution
of disease and were
symptom free at the
last follow-up
McAfee 22 Definitive RT, dose from 30 20 patients (91%) Median follow-up, 12.7
et al. (2006) to 36 Gy remained locally years
controlled after RT
2 patients with local
recurrence were
salvaged—ultimate
local control: 100%
Park et al. 1 Recurrent JNA Mass disappeared
(2006) post-surgery almost completely
Radiosurgery 17 Gy without any
delivered to the 50% complications in the
isodose line 4-year follow-up
Lee et al. 130 102 treated with surgical 15% (4 of 27) of Long-term complications in
(2002) resection; 1 refused irradiated patients 4 patients (15%): growth
treatment; 27 received developed recurrent retardation,
radiation tumor 2–5 years later panhypopituitarism,
Cobalt 60 or linear 3 of the 4 were treated temporal lobe necrosis,
accelerators: RT doses with a second course of cataracts, and radiation
from 3000 to 5500 cGy radiation (20–45 Gy) keratopathy
After 1986, RT doses from and have had no
3600 to 3960 cGy evidence of recurrence
after 2–7 years of
follow-up
Kuppersmith 3 2 patients diagnosed with Tumor response in all
et al. (2000) recurrence at 11 and 13 cases
months postoperatively No endoscopic
1 patient surgically evidence of disease in
unresectable 2 cases at 15 months
IMRT dose 34–45 Gy and 40 months
Total number
Ungkanont 43 Surgery only (32) 14 recurrences, Median follow-up of 29
et al. (1996) Surgery + chemotherapy including 1 treated months
(4) with RT Patients treated with RT
Chemotherapy only (3) had stage IV disease, with
RT only 35 Gy (2) anterior cranial fossa or
Surgery, RT, and cavernous sinus
chemotherapy, 45 Gy (1) involvement
Observation (2)
Kasper et al. 9 RT (2) 2/7 CR, local control Minimum follow-up 3
(1993) Surgery + RT for 100% years
recurrence (7)
All 3000 cGy 180 cGy, 4
1/2 weeks 19–22 fx
Fields et al. 13 2 pts. RT upfront 11 Control 85% said to be Mean follow-up 136
(1990) patients surgery, then RT comparable to months
3600–5200 cGy Cummings. Poorly
2 pts. embolized analyzed
Cummings 46 3000–3500 cGy 80% initial control 3–26-year follow-up
et al. (1984a) extracranial 2 intracranial required a 6 recurrences
9 second course radiation controlled
intracranial
Hawkins III 10 Surgery (9) Extracranial recurrence 8 patients had stage IIIb, 1
(1980) RT 30 Gy EBRT (1) in 2/9 surgical patients had stage IVa, and 1 had
(22%) stage IVb
RT: If the tumor was not
visible on follow-up,
MRI 3 years
post-RT. No recurrence
during 20-year follow up
Vadivel et al. 7 3000 rad in 3 weeks. 6 of 7 patients Follow-up 2–9 years.
(1980) 6480 rad in 8 weeks receiving doses of Nasopharynx 13–22 years
>3000 r/3 weeks
rendered free of
disease
Jafek et al. 15 Surgery with resection, 60% no evidence of Intracranial nasopharyngeal
(1979) radiation of 3000–4000 rad disease 3–14 years masses 5–18 years
of residual tumor 3 months posttreatment
postoperatively
Sinha and 7 3000–3600 rad in 3 weeks Good results, no side Nasopharynx 15–20 years
Aziz (1978) effects
Biller et al. 43 Surgery, if persistence 61% of cases revealed Nasopharynx 6–20 years
(1974) through radiotherapy persistence following
surgery alone
A planned treatment
course with surgery and
radiotherapy controlled
93% of patients
Kadin et al. 1 Radiotherapy: Follow-up at 8 months Patient had extensive
(1974) 4500 rad/10F/4.5 weeks. revealed little visible nasopharyngeal fibroma
6 MeV, parallel opposed tumor. Angiograms with extension into the left
lateral fields showed residual mass infratemporal space, left
to be smaller and less orbit, sphenoid sinus, and
vascular. Also extension floor of the middle (left)
into the orbit and cranial fossa. Patient was
middle cranial fossa 14 years of age
was no longer evident.
No significant regrowth
at 2-year follow-up
Total number
Jereb et al. 69 1. Surgery only (3) 57/63 free of disease Radiation damage:
(1970) 2. Radiotherapy (pre-op) for 5 years or more Atrophic changes in skin or
and surgery (2) nasal mucosa (31)
3. Surgery, radiotherapy Cataract (2)
for recurrence (14) Osteonecrosis (1)
4. Radiotherapy alone
(50). The majority of
patients receiving
radiotherapy received
2000–6000 rad
Wang (1970) 3 Radiation (pre-op) No recurrences 4–8 Age range of patients was
followed by surgery. Dose: years after treatment unusual: 31–58 years
4500–5000 rad/31–37 days
One patient received two
courses of radiation prior to
surgery
McGavran 30 1. Transnasal piecemeal Recurrence:
et al. (1969) avulsion, primary (15), 1. 10/15 primary,
after recurrences (14) 12/14 after previous
2. Transpalatine excision, recurrences
primary (10), after 2. 4/10 primary, 3/5
recurrences (5) after previous
3. Caldwell-Luc excision recurrences
or lateral rhinotomy, 3. 2/4 primary, 6/10
primary (4), after after previous
recurrences (10) recurrences
4. Radiation, primary (1), 4. 1/1 primary, 0/3
after recurrences (3) after previous
recurrences
Conley et al. 38 1. Radiation (4) 1. 2/4 control 1. Radionecrosis of the
(1968) 2. Radiation (pre-op) and 2. 3/3 free of tumor maxilla (1) and squamous
surgery (3) 3. 17/34 tumor cell epithelioma of the face
3. Surgery alone (34) remaining and orbit developed 18
Total of 55 operative years after irradiation (1).
procedures were done Complications in 13
patients: osteomyelitis,
severe post-irradiation
bleeding, severe bleeding
following biopsy, persistent
palatal fistulas (2),
hypotension and
hypovolemia leading to
cardiac arrest (2),
meningeal irritation (2),
dacryocystitis (1), hepatitis
and nephritis (2), post-op
death (1)
Fitzpatrick 37 Radiotherapy: 31/37 control: usually 18/37 had previous surgery.
(1967) 3000–3500 rad/14–16 F/3 early symptomatic Of the 6 who were not
weeks with supervoltage relief. Objective tumor controlled by surgery, 2
irradiation in the majority regression often took were controlled after a
of cases many months second course of
irradiation, 2 by subsequent
surgery and radiotherapy,
and 2 by subsequent
surgery alone
5 Choroid Plexus Papilloma Gross tumor resection of CPP is associated

with favorable clinical outcomes and is the rec-
Choroid plexus papillomas (CPP) are rare, slow- ommended treatment approach, with rare recur-
growing lesions of the choroid plexus that arise rences (Wrede et al. 2009). However, due to the
within the ventricles or cerebellopontine angles. tumor location and proximity to the brain stem,
While most cases arise in the ventricles (predilec- gross total resection is frequently unachievable
tion for the third and fourth ventricles), extraven- (Golabek et al. 2019). Up to 50% of patients
tricular cases have also been reported (Koh et al. recur after subtotal resection (Krishnan et al.
2014; Lozier et al. 2009). As per the World Health 2004). The role of postoperative radiotherapy in
Organization, CPP are part of a spectrum of his- the context of subtotal resection is controversial.
tological grades: grade I for CPP, grade II for Due to the risks of late radiation-induced compli-
atypical CPP (aCPP), and grade III for choroid cations in this generally young patient popula-
plexus carcinoma (Louis et al. 2016). CPP are tion, several authors favor avoidance of
more common (5:1 ratio) than choroid plexus radiotherapy after subtotal resection and close
carcinomas. Patients with CPP present typically observation, with salvage surgery at the time of
at an older age (median age 25 years) compared recurrence. Localized radiotherapy, using stan-
to the carcinoma counterpart (median age 3 dard fractionation to a total dose of 50–54 Gy or
years) (Cannon et al. 2015). Choroid plexus stereotactic radiotherapy, has been described in
tumors may cause an overproduction of cerebro- some reports at the time of recurrence (Krishnan
spinal fluid, leading to increased intracranial et al. 2004).
pressure presenting most commonly with head-
aches, nausea, and/or vomiting.
Total
number of
Faramand 32 25 had initial surgical resection Local control 69%; PFS
et al. (2021) SRS median dose 13 Gy, maximum rates for low-grade
dose 25.5 Gy tumors at 1, 3, and 5
years were 90%, 77%,
and 58%, respectively
Dudley et al. 107 90% underwent surgical resection More than 98% alive at Based on SEER
(2015) pediatric 64% had GTR the last follow-up database 2004–
patients RT in 0.9% 2010. Median
follow-up: 38
months
Jafek et al. 8 GTR (7) No recurrence Median follow-up:
(1979) STR + SRS (1) 38 months
Krishnan 41 GTR in 46% LC 100% vs. 68% for Median follow-up
et al. (2004) STR in 44% GTR vs. STR (p = 0.04), was 6.5 years
PORT in 4 patients with STR no diff in OS 100% vs.
(55.8 Gy, 56 Gy, 29.4 Gy, 43.8 Gy) 94%
3 patients with relapses post-STR
had RT without further surgery:
• Palliation to spine and local
recurrence (1)
• SRS 18 Gy to 50% IDL (1)
• RT + chemotherapy (1)
Cannon et al. 203 CPP 5 patients with CPP had EBRT 5-year OS CPP: 90%, Based on SEER
(2015) (26 aCPP) aCPP: 77% database
1978–2009
Median follow-up
26 months
Total
number of
Talacchi 12 Standard EBRT (5) 2 had tumor progression Mean follow up:
et al. (1999) SRS (3) patients; 2 of them after and died during the 8.2 years
recurrences follow-up
Duke et al. 1 GK SRS 10 Gy No recurrence at 17
(1997) months
McGirr et al. 26 14 Gross total resection alone 5/26 Recurred
(1988) 12 Subtotal resection (8/12 subtotal 17/26 NED
resection had adjuvant RT) 4 died in perioperative
period
Aristizabal 1 Biopsy, 4500 r in 30 fractions in 43 No neurologic deficits at Surgically
and Runyon elapsed days 3-year follow-up. unresectable
(1981) Continued decrease in
size on follow-up CT
scans
Naguib et al. 1 Subtotal excision, 4950 r in 32 At 16-month follow-up,
(1981) fractions in 33 days regression of tumor size
Hawkins III 17 Surgical excision. Postoperative Five children underwent Response to
(1980) radiation therapy for those radiation, with preoperative
incompletely resected, and those persistence of neurologic radiation allowed
malignant histologically; 3000– deficits resection in 1 case
4000 r given
6 Pheochromocytoma extra-adrenal paragangliomas secrete catechol-

and Extra-adrenal amines and can present with hypertension, palpi-
Paraganglioma tations, headaches, sweating, or tachycardia,
among other signs.
Pheochromocytomas and extra-adrenal paragan- Surgical resection is the treatment of choice
gliomas are rare neuroendocrine tumors arising for pheochromocytoma and extra-adrenal tumors
from the sympathetic and parasympathetic para- (Chen et al. 2010a). There is scarce data on the
ganglia (Lenders et al. 2005). Chromaffin- role of radiotherapy for pheochromocytomas and
positive tumors refer to pheochromocytomas and intra-abdominal/thoracic paraganglioma. On the
extra-adrenal sympathetic paragangliomas (typi- contrary, radiotherapy has historically played an
cally located in the abdomen, pelvis, or thorax) important role in head and neck paragangliomas
(Lenders et al. 2005), in contrast to non- given the complex anatomical location and risks
chromaffin tumors which refer to extra-adrenal associated with surgery (McCabe and Fletcher
parasympathetic paragangliomas (most located 1969; Li et al. 2007). With recent improvements
in the head and neck and also referred to as che- in surgical and imaging techniques, embolization
modectoma, glomus jugulare, or carotid body followed by surgical resection is now often con-
tumor) (Chen et al. 2010a). As per the World sidered the treatment of choice. Radiotherapy
Health Organization, these tumors are classified continues to play an important role in selected
as pheochromocytomas, arising from the adre- cases, either as adjuvant or as definitive therapy.
nals exclusively, and extra-adrenal paragangli- Radiation doses between 40 and 50 Gy in
oma, which includes all extra-adrenal paraganglia 1.8–2 Gy per fraction lead to local control rate of
(sympathetic or parasympathetic) (DeLellis et al. around 90% (Kim et al. 1980; Huy 2014; van
2004). Pheochromocytomas and sympathetic Hulsteijn et al. 2013). For small intracranial para-
ganglioma, stereotactic radiosurgery or fraction- 2006). For treatment of inoperable or metastatic

ated stereotactic radiotherapy achieves similar pheochromocytomas and paragangliomas, pep-
local control (Guss et al. 2009; Pollock 2004; tide receptor radionuclide therapy can be used
Shapiro et al. 2018; Zabel et al. 2004). given the overexpression of somatostatin recep-
Radiotherapy typically leads to stabilization of tors displayed by these tumors (Tsang et al. 2021;
tumor growth and symptoms, and improvement Severi et al. 2021).
of symptoms in about 20% of cases (Krych et al.
6.1 Pheochromocytoma
and Abdominal/Thoracic
Paraganglioma
Total
number
of
Gonzalez 1 SBRT 24 Gy in 3 Patient’s symptoms Died 1 year later from convulsive
et al. fractions to adrenal improved and blood episodes and hemodynamic
(2021) recurrence of pressure stabilized instability. Brain imaging showed
pheochromocytoma nodular lesions suspected to be
cerebellar hemangioblastomas
Simpson 1 C7, T1, and T2 Symptom free without Primary paraganglioma of the
et al. laminectomy; tumor evidence of disease thoracic spine
(2012) debulking, adjuvant progression at 2 years
EBRT (45 Gy)
Brantigan 3 1. Surgery plus 1. Good initial response Paraganglioma of the organ of
and Katase radiotherapy but metastases noted Zuckerkandl
(1969) (1 patient) 2 years later
2. Surgery only 2. Patient was
(1 patient) hypertensive without
3. Radiotherapy only recurrence or
(1 patient) metastases noted; lost
to follow-up 8 years
later
3. Patient remained
normotensive for 2
years until he died.
An autopsy tumor of
the organ of
Zuckerkandl was
found
6.2 Head and Neck Paraganglioma
Total
number of
Anderson et 30 SRS/SBRT (14–18 Gy in 1 LC 100% Median follow-up 4.2 years
al. (2020) fx; 21–28 Gy in 3 fx; 87% had a reduction in
22.5–30 Gy in 5 fx) or volume
IMRT (45–54 Gy in 15–27 77% of patients had
fx) in the definitive, improvement in at least
adjuvant, or salvage setting one tumor-induced
symptom
Lior et al. 23 SRS median dose 14 Gy in Tumor reduction in 13
(2020) 1 fx patients and stable
volume in 8
91% tumor control rate
Weissmann et 40 FSRT median dose was Local control rate was Median imaging follow-up
al. (2019) 54 Gy (range, 50.4– 100% of 52.2 months
56.0 Gy) in 1.8 or 2 Gy/fx
Sallabanda et 30 12–14 Gy in 1 fx; OS rate 97% Mean follow-up 4.6 years
al. (2018) patients 24–27 Gy in 3 fx Local control rate 97%
(31
tumors)
Sharma et al. 42 SRS median dose to the 5- and 10-year local Median follow-up 62.3
(2018) patients tumor margin 15 Gy control rates 87% and months
(43 (12–18 Gy) 69% New onset or worsening of
tumors) hearing loss in 6 patients
Ibrahim et al. 75 Median SRS dose 18 Gy Tumor control rate 93.4% Median radiological
(2017) patients (range 12–25 Gy) follow-up 51.5 months
(76 (range 12–230 months)
tumors) Improvement of preexisting
deficits was noted in 15
patients (20%)
Winford et al. 38 SRS mean dose to tumor 88% of tumors decreased Glomus jugulare
(2017) margin 13.2 Gy in size or remained stable Mean follow-up 39.1
months
El Majdoub et 27 SRS as primary or salvage 10 of 27 had significant Median follow-up 11 years
al. (2015) therapy improvement of
Median therapeutic single neurological complaints,
dose applied to the tumor 12 remained unchanged
surface was 15 Gy (range No tumor progression
11–20 Gy) OS rates at 5, 10, and 20
years were 100%, 95.2%,
and 79.4%
Liscak et al. 46 Radical SRS (37%) Tumor size decreased in Median follow-up 118
(2014) Surgery + SRS (46%) 77% months
Surgery + fractionated RT Increase in volume in 1
(4%) patient (182 months after
SRS median dose to tumor radiosurgery)
margin 20 Gy
Chun et al. 31 SRS 25 Gy in 5 fx Local control and OS rate Median follow-up 24
(2014) 100% months
Of 20 patients with
tinnitus, 12 reported
improvement, 6 reported
complete resolution
Total
number of
Dupin et al. 66 EBRT median 45 Gy/25 fx 5-year LC 100% Median follow-up 4.1 years
(2014) patients (range, 41.4–68 Gy) 10-year LC 98.7% 2 late vascular
(81 20/66 had salvage radiation complications (middle
tumors) therapy cerebral artery and carotid
stenosis)
2 late radiation-related
meningiomas at 15 and 18
years
de Andrade et 15 SRS dose to the tumor Neurological status One patient developed a
al. (2013) margin ranged between 12 improved (3) or remained transient seventh nerve
and 20 Gy unchanged (12) palsy that improved after
All tumors remained clinical treatment
stable in size on
follow-up with resonance
magnetic images
Combs et al. 39 SRS or IMRT 10-year LC 97%
(2014) Re-RT (5, 13%) 10-year OS 87%
Primary treatment: Clinical symptoms
• Surgical resection (16, improved in 18 patients
41%) (46%)
• Embolization (4, 10%) Unchanged in 10 patients
• RT (19, 49%) (26%)
SRS 18 Gy/80% isodose
IMRT median dose
57.6 Gy
Wegner et al. 18 56% previously untreated Tumor stable in 17 Median follow-up 22
(2010) 44% persistent after patients and decreased in months
surgical resection size in 1 patient
1 had previous EBRT LC 100%
2 had previous GK SRS
SBRT median dose 20 Gy
in 3 fx (range: 16–25 Gy in
1–5 fx) to 80% isodose line
Genc et al. 18 SRS mean marginal Tumor control in 17/18 Mean follow-up 52.7
(2010) radiation dose was 15.6 Gy patients (94.4%) months
(median 15 Gy, range
13–20 Gy)
Chen et al. 15 Mean dose to the tumor Tumor control 90.5% Mean follow-up 43.2
(2010b) margin 14.6 Gy months
Lightowlers et 21 EBRT 50 Gy in 30 5-year LC was 95% Median follow-up 55
al. (2010) fractions (20/21) months
Huy et al. 88 EBRT (41) mean dose of Surgical resection, total Mean follow-up 66 months
(2009) 45 Gy (range, 44–50 Gy) or subtotal, yielded an for surgery, 50 months for
Surgery alone (47), total or overall 86% rate of either EBRT
subtotal cure or tumor
stabilization.
Radiotherapy achieved
local control in 96% of
patients
Total
number of
Chino et al. 31 EBRT median dose: 54 Gy, LC at 5, 10, and 15 years Median follow-up 9 years
(2009) range: 38–65 Gy was 96%, 90%, and 90%, (range: 2–35 years)
Megavoltage photon (12) respectively
Cobalt-60 or cesium-137
(19)
14 (45%) had undergone
resection before RT
Hinerman et 71 Previously untreated (66) Local control 94%
al. (2008) patients Prior treatment (surgery, 11 5 local recurrences at 2.6
(80 lesions; RT, 1; or both, 2 years, 4.6 years, 5.3
tumors) lesions) years, 8.3 years, and 18.8
EBRT: 45 in 25 (13 years
patients)
35 in 10 and 45.8 in 29
Re-RT 40.8 in 34 BID
Malignant: 64.8 in 36; 70
in 39
Henzel et al. 17 Previous surgery (11) 5 year Freedom from Median follow-up 40
(2007) Primary RT (6) progression and overall months
Fractionated SRT: median survival for 5 years were
dose 57.0 Gy (range, 100% and 93.8%.
52.5–65.0 Gy); Daily dose Radiologic regression
1.8–3.5 Gy (median was seen in 5/16 cases,
2.0 Gy) 11/16 patients were stable
Gerosa et al. 20 Previous treatment: Tumor volume stable (11) Mean follow-up
(2006) Surgical recurrences (8) Or slightly (≤20%) 50.85 months
SRS (3) decreased (8)
Embolization (11)
SRS mean dose 17.3 Gy
(range, 13–24 Gy)
Krych et al. 33 EBRT or SRS 10-year tumor control Median follow-up of 13
(2006) rate 92% years
Pemberton et 49 2D wedge pair in majority 10-year recurrence-free Median follow-up 7.4 years
al. (2005) Median dose of 45 Gy survival rate: 92%
(range, 37.5–50.0) in 15 or 10-year cancer-specific
16 fractions survival rate: 96%
Zabel et al. 22 Primary RT (10) 5- and 10-year OS rate Median follow-up 5.7 years
(2004) Recurrent or progressive was 89.5%
disease after primary 5- and 10-year LC rate
surgery (8) or embolization 90.4%
(4) Partial response (7)
Median dose 57.6 Gy, in Stable disease (13)
1.8 Gy/fraction Neurologic dysfunction
improved or completely
resolved in 59% and
stabilized in 32%
Lim et al. 13 (16 SRS 14–27 Gy All tumors remained Mean follow-up period 60
(2004) tumors) stable or decreased in size months
on follow-up MR images
Elshaikh et al. 29 Surgery (17) 5-year freedom from Median follow-up 55
(2002) Salvage RT (12) disease progression: months
SRS (7) 100% in patients treated
Conventional EBRT (4) with RT vs. 62% in those
IMRT (1) treated with surgery
(p = 0.0124)
Total
number of
Foote et al. 25 SRS 12–18 Gy 17 tumors remained Median follow-up 35
(2002) stable and 8 decreased in months
size
de Jong et al. 38 RT primary modality (14) LC: 79% in RT primary Temporal bone
(1995) Surgery + RT (13) modality, 100% in paragangliomas
RT as salvage (11) surgery + RT, 91% in Median follow-up 11.5
salvage RT years
Mertens et al. 23 Previous surgery, radiation, 1 year of improvement
(1993) now chemotherapy,
Cytoxan, and vincristine
Powell et al. 84 EBRT 45–50 Gy Skull base 73% 25 years,
(1992) neck 54% 15 years
Verniers et al. 22 50 Gy, 25 fx 88%: 10 years Historic table, 399 patients,
(1992) 91% control
Skolyszewski 24 30–60 Gy 23/24 local control No complications
et al. (1991)
Pryzant et al. 20 22–50 Gy No local failure
(1989) 45 Gy most common No complication
1 dissemination
Wang et al. 32 29–67 Gy or surgery 84% controlled. 2
(1988) operations
34% complications
84% controlled radiation
and
11% complications
78% survived surgery
77% survived radiation
Konefal et al. 26 40–50 Gy Local control 100%
(1987) 4/25 died of disease
Zinreich and 15 4500–5000 r brain stem Surgery alone 6/7 No complications. 2–10
Lee (1986) limit 4500 r NED. Seventh salvaged year follow-up
by RT
8/8 Surgery plus radiation
NED
6/6 Radiation alone NED
(personal
communication)
Cummings et 45 (aged Radiotherapy: 3500 r/3 No deaths from tumors. 2/23-year follow-up. 14
al. (1984b) 17–81) weeks 3/45 not controlled; references are reviewed in
symptomatic relief tabular form with
achieved in majority 3000–6500 r given
Total
number of
Lybbert et al. 28 Radiotherapy: 4000/6000 r All patients had tumor 1.5–18-year follow-up
(1984) (mean control
age 42)
Sharma et al. 42 Radiotherapy: 3000/8000 r Tympanic (92%) Complications: 4
(1984) (author recommends 22/24 controlled. Jugulare osteoradionecrosis: (2
5000–6500 r) 11/16 (69%) controlled received >8000 r, 1 had
7 patients no local control 5000 r plus radium, 1 had
with dose 3000–4000 r 4000 r plus infection)
Reddy et al. 17 Surgery and/or 16 patients alive and All glomus jugulare
(1983) radiotherapy disease controlled tumors. Follow-up 2–22
years
Dickens et al. 18 Radiotherapy: 3700/5600 r All irradiated patients had
(1982) regression
Of 8 patients with cranial
nerve paralysis, 5
recovered
Kim et al. 40 Radiotherapy with/without Postoperative XRT: 85% Analysis of literature 22%
(1980) (mean surgery control recurrence with <4000 r/4
age 54 weeks
(15–78)) 4000 r postoperative Definitive XRT: 88% 2% recurrence with
control >4000 r
5000 r inoperable Follow up: 5–30 years
Arthur (1977) 26 Radiotherapy: 4500/5000 r 2 tumor recurrences
Others: disease free
1 recurrence in patient
who received 3000 r
Spector et al. 15 1. Irradiation alone (10). 1. 3/10 no visible tumor All were glomus jugulare
(1975) 4600–6000 r Co60 tumor tumors
dose Follow-up of 2–27 years
2. Postoperative irradiation 2/10 persistent but
(5) 5000–7000 r Co60 tumor smaller. 2/10 persistent,
dose no progression
3. Preoperative irradiation 3/10 recurrent (were later
(5) 4600–6000 r Co60 tumor successfully treated by
dose surgical resection)
2. 2/5 no visible tumor
3/5 recurrent
3. 4/5 no visible tumor.
1/5 recurrent
Total
number of
Tidwell and 19 1. Surgery alone (2 1. 1 patient alive and free All were chemodectomas
Montague patients) of disease at 13 years of the temporal bone
(1975) following treatment. 1
patient had a recurrence
at 110 months for which
he received radiotherapy
but died with intracranial
extension 18 months later
2. Radiotherapy (17 2. 16/17 no recurrence at
patients) after biopsy or 4–18-year follow-up
partial excision. Tumor 1/17 died 3 years
dose of 4500–5000 r in following radiotherapy.
4.5–5 weeks Autopsy showed
Technical details: encephalomalacia in the
Co60 anteroposterior or right temporal lobe, pons,
superoinferior wedged right cerebellar lobe, and
filters (16 patients) focal necrosis at the right
22 MeV X-rays and occipital lobe
10 MeV electrons through
a single lateral field (1
patient)
Total
number of
Bundi (1974) 25 Glomus jugulare tumors Glomus jugulare tumors: Location of
(19): 3/19 died, all had cranial chemodectoma: glomus
Radiotherapy preceded by nerve involvement at jugulare (19), carotid body
biopsy/exploration of the death. Carotid body (4), aortic body (1), larynx
ear or mastoidectomy (18 tumors: (1)
patients) 2/4 died
1 patient received no
treatment. 4500–6000 r/24–
43 days, 4 MeV in most
cases
Carotid body tumors (4): Aortic body tumor:
Patient developed
adenocarcinoma of the
breast 1 year later.
Histology of the breast
tumor and mediastinal
tumor was not the same
Radiotherapy, 5000– Chemodectoma of the
6000 r/26–32 days, larynx:
orthovoltage or
megavoltage
Aortic body tumor: Recurrence following
surgery
Radiotherapy, Patient continued to
5055 r/20 F/28 days, deteriorate and died 2.5
4 MeV years following partial
laryngectomy
Chemodectoma of the
larynx:
Section of the ninth cranial
nerve followed by right
partial laryngectomy 3
years later. Recurrence
treated with radiotherapy,
6000 r/30 F/39 days,
4 MeV
Jackson and 63 1. Radiotherapy at any time 1. 14/23 (61%) primary 4 patients receiving
Koshiba during treatment (i.e., control at 5 years radiotherapy as primary
(1974) pre-op, post-op, or primary treatment died from
treatment) possible cerebral necrosis
2. Radiotherapy as first 2. 8/14 (57%) primary caused by high-dose
treatment control at 5 years radiation
3. Megavoltage X-ray 3. 12/17 (71%) primary
therapy at any time during control at 5 years
treatment
4. Megavoltage X-ray 4. 8/9 (89%) primary
therapy as first treatment control at 5 years
Details of radiotherapy:
4500 r/21 days
Spector et al. 19 1. Radiation (10) 1. 8/10 tumor persistence All were glomus jugulare
(1974) 2. Pre-op radiation and 2. 0/4 tumor persistence tumors. This series includes
surgery (4) some of the patients in the
3. Post-op radiation and 3. 3/5 tumor persistence previously published series
surgery (5) by Spector et al.
Total
number of
Moore et al. 31 Group 1 (tympanic): Group 1:
(1973) 1. Total resection (8) 1. 7/8 no progression at
3–12 years. 1/8 recurred
at 2 years
2. Total resection plus 2. No progression at 14
radiotherapy (1), years
3600 r/16 F/3 weeks
3. Subtotal resection plus 3. Progressive disease to
radiotherapy (1) death 30 years later
4. Biopsy only (1) 4. Alive at 2 years
Group 2 (tympanomastoid): Group 2:
1. Total resection (3) 1. 2/3 no progression at 2
and 12 years. 1/3 recurred
2. Total or subtotal 2. 3/3 no progression at 4,
resection plus radiotherapy 10, and 12 years
(3), (3000 r/16 F/3 weeks
to 6054 r/30 F/6 weeks)
3. Biopsy only (1) 3. Alive at 3 years
Group 3 Group 3:
(petrosal-extrapetrosal):
1. Total resection (3) 1. 2/3 recurred
2. Total or subtotal 2. 5/5 no progression at
resection plus radiotherapy 1–15 years
(5). 3150–5500 r/18–
25 F/3–5 weeks
3. Radiotherapy plus 3. 5/5 no progression at
biopsy in some cases (5) 1–9 years
3900–5500 r/25–29 F/5
weeks
Newman et al. 20 1. Surgery only (14) 1. 11/14 recurred (10 All were tumors of the
(1973) within 3 years). middle ear
Recurrences treated by 1 lost to follow-up
radiotherapy: 7/8 no 2 died of other causes
clinical evidence of Most common surgical
disease at follow-up of 5 complication was damage
months–10 years to the facial nerve
2. Radiotherapy followed 2. No recurrences at 4 No findings of cerebral
by surgery (2) and 7 years post-op necrosis
3. Surgery followed by 3. No evidence of disease
planned radiotherapy (2) at 5 and 7 years post-op
4. Radiotherapy only (2). 4. No evidence of disease
Details of radiotherapy: at 18 months in one
4600–5500 r/6–8 weeks patient. Symptoms
improved in the other
patient but was lost to
follow-up at 4 months
Total
number of
Rosenwasser 30 Lesions with extensive Glomus jugulare tumors
(1973) involvement of the middle
ear, mastoid, and temporal
bone:
1. Irradiation only (10 1. 4/10 alive, no
patients) symptoms except for
tinnitus in 2 patients. 1/10
was asymptomatic for 20
years but has trouble now.
3/10 died with persistent
disease. 1/10 alive, less
bleeding. 1/10 lost to
follow-up
2. Surgery plus irradiation 2. 1/4 well with no
(4 patients) evidence of disease at 5
years. 2/4 symptom free
at 3–10 years. 1/4 died
with persistent recurrent
disease
3. Surgery only (2 patients) 3. 1/2 died. 1/2 doing
Lesion confined to middle well, but surgery involved
ear and mastoid bones local removal of ear
4. Radical mastoidectomy 4. 11/12 well (9 have no
(12 patients) persistent or recurrent
disease). 1/12 died
5. Radical mastoidectomy 5. 1/2 well. 1/2 recurred,
plus irradiation (2 second course of
patients) irradiation, is now
An additional 1000 r was symptom free
later given to the
nasopharynx, posterior
nasal cavity, and sphenoid
sinus
Spector et al. 46 1. Surgery alone (25 1. 73% no recurrence All were tumors of the
(1973) patients) middle ear. Resectable
2. Surgery followed by 2. 40% no recurrence lesions were operated on as
radiotherapy (5 patients) the first choice of therapy.
3. Radiation only (10 3. 20% no recurrence Unresectable lesions and
patients) patients in poor health
received radiation
Hatfield et al. 32 1. Irradiation only (4) Recurrences: 1. All patients in this group
(1972) 1. 0/4 were inoperable
2. Surgery plus post-op 2. 3/12 2. 10/12 were incompletely
irradiation (12) excised
3. Surgery only (16) 3. 8/16 (7 of these
Details of radiotherapy received radiotherapy for
3000–4500 r Co60 through recurrence)
one or more portals
2 MeV or Co60. Wedged
fields
Total
number of
Westbrook et 20 Resection (18 patients) Complications: Chemodectomas of the
al. (1972) One patient refused surgery Mortality (0) neck: the majority were
One patient was only CNS damage (0) carotid body tumors.
observed Authors stated that they
Permanent nerve damage would employ irradiation
(6) in patients who refuse
surgery or have
Auriculotemporal
unresectable, residual, or
syndrome (2)
metastatic disease
Pain in temporal
mandibular joint (2)
Radiotherapy 5000 r/5
weeks, Co60
Oberman et 40 Carotid body and vagal Carotid body and vagal Chemodectomas of the
al. (1968) body tumors: body tumors: head and neck. Location:
1. Excision (10 patients, 7 1. 1/10 recurred, treated Carotid body (14)
of these had carotid body by radiotherapy, and was
tumors, 3 had vagal body asymptomatic for the
tumors) subsequent 6 years
2. Subtotal excision (6, all 2. 4/6 recurred Glomus jugulare (23)
carotid body tumors)
3. Radiotherapy (1 carotid 3. No regression Vagal body (3)
body tumor)
Glomus jugulare tumors: Glomus jugulare tumors:
4. Resection through a 4. 2/6 recurred
lymphadenectomy (6
glomus jugulare tumors)
5. Mastoidectomy or 5. 1/7 recurred
diagnostic biopsy plus
radiotherapy (7)
6. Radical mastoidectomy 6. 6/10 recurred
(10)
4500 r/l month, Co60 and
20 MeV. Subsequent
excision
7 Cystic Hygroma, controlling these lesions or they are located in a

Lymphangioma site where complete excision is not possible.
Radiation therapy is generally considered inef-
Lymphangiomas are benign neoplasms of the fective for lymphangiomas. However, in rare cir-
lymphatic system considered to be developmen- cumstances for tumors in unusual locations, and
tal lymphatic malformations. Lymphangioma in refractory symptomatic patients, radiation
occurs either after damage to previously normal therapy may be indicated. Low doses in the range
lymphatics or as a congenital abnormality. of 15–20 Gy appear to be effective in preventing
The accepted appropriate therapy is surgical continual chylous effusion and in reducing the
excision. However, when they are incompletely lesion.
excised, recurrence is common. Occasionally,
repeated surgical procedures are unsuccessful at
7.1 Cystic Hygroma Radiotherapy

and/or Surgery
Total
number
of
Yildiz et al. 1 EBRT Dramatic objective Persistent vulvar
(2008) 20 Gy in conventional response with relief of lymphangioma
fractionation all symptoms circumscriptum despite
sclerosing therapy and
several surgical
excisions
Denton et al. 2 1: 12.5 Gy to the 90% isodose Marked reduction of size Lymphangioma
(1996) was given in five fractions with and pigmentation at circumscriptum
8 MeV electrons 6-month and 1-year unresectable lesions
2: 10 Gy prescribed to the 90% follow-up
isodose with 12 MeV electron
Tai and 1 RT (15 Gy/15 fractions/3 weeks Good response, Unresectable massive
Jewell followed by a boost of 5 Gy/4 maintained after 10 mixed hemangioma and
(1995) fractions/4 days) years lymphangioma of the
mesentery
Behrendt et 1 Strontium-90 6 fractions of 5 Gy, No progression at 2-year Conjunctiva
al. (1991) 30 Gy total follow up
Ikemura et 1 (case Co60, 20 Gy given as 100 cGy No change after 20 Gy. Surgical excision
al. (1987) report) qod: then 4 months later At 3-year follow-up, had initially, followed by
3 years additional 10 Gy given. Total complete remission by recurrence.
old 30 Gy physical exam and Radiotherapy given for
radiographic exam recurrence, when
symptomatic
Johnson et 1 Posterior mediastinum, 11 years Unsuccessful surgical Prompt and permanent
al. (1986) management, followed resolution of the
by 2000 cGy/10 chylothorax. No
fractions mediastinal recurrence with 2-year
radiotherapy follow-up
O’Cathail et 1 800 cGy to the lateral chest wall Slow durable remission
al. (1985) of the lesions
Total
number
of
Aristizabal 1 Peritoneum No evidence of disease Peritoneum
and Runyon 2600 r whole abdomen followed at 6-year follow-up Three previously
(1981) by 1400 r whole pelvis unsuccessful surgical
attempts prior to
radiotherapy
Aristizabal 1 (case Ovary, involving peritoneal 2600 cGy whole NED at 46 months
et al. (1977) report) cavity, 27 years abdomen, followed by Same case as reported
1400 cGy to whole by Aristizabal and
pelvis Runyon (1981). Patient
had 3 prior unsuccessful
surgical procedures
Stromberg et 3 Radiation therapy No response when used
al. (1976) as initial therapy or
subsequent therapy
Saijo et al. 1 Lip and cheek, age 3 Radon seeds No visible swelling or
(1975) facial asymmetry, no
bone abnormality at age
41, 38 years of
follow-up
Kopperman 1 (case Bone-calvarium/27 years 2000 cGy in 5 days Regression
and Antoine report) No follow-up data
(1974) provided
Ninh and 7 Radiotherapy (no details) No improvement. All Lymphangitis and
Ninh (1974) were subsequently lymphedema
operated on
Barrand and 2 Radiotherapy Caused an increase in
Freeman size which necessitated
(1973) urgent surgery
Galofre et al. 57 Radiotherapy (X-irradiation, 17/35 (48%) good Authors emphasized
(1962) radium, or radon seeds) results that the “good” results
in the nonsurgical group
were not as good as the
correspondingly labeled
ones in the surgical
category. Such things as
atrophy of the face,
problems in dental
development, and
actinodermatitis were
common complications
in the nonsurgical series
Perzik 1 External and interstitial Continued enlargement Age 3 1/2 months.
(1960) irradiation and injections of after treatment with Cervical cystic hygroma
sclerosing solution. Surgical irradiation and
excision sclerosing agents.
Several episodes of
recurrent infection
post-op. Subsequent
satisfactory regression
Total
number
of
Martin 9 Radium applicator therapy 7/9 satisfactory response Retarded development
(1954) (usually 900 mg h repeated 2–3 (but three of these of right shoulder girdle
times) and/or radiotherapy required plastic surgical and breast in one patient
(900–2400 r/5–9 days, 200– repair after treatment to receiving radiotherapy
220 kV). Prior partial surgical remove redundant skin to the axilla and
excision in one case folds) supraclavicular area
Pfahler and 1 2400 r (air) 8 F/5 months. Progressive reduction of Mass involved neck and
Perlman Additional intermittent treatments the mass mediastinum
(1950) in the next 2 years to bring the
total surface dose to 4000 r.
Technical factors: 180 kV,
15 mA, 0.5 mm Cu plus 1 mm A1
filtration, FSD, 50 cm. Three
portals: anterior neck and chest,
posterior neck and chest, and
right axilla
Portmann 1 600 r/6 F/6 weeks to each side of Cervical masses began Age 10 months. Mass
(1945) the neck and mediastinum. Field to diminish in size, but involved neck and
size: 10 × 10 cm. Technical surgery was attempted mediastinum
factors: 200 kV, HVL, 0.9 mm elsewhere. Child died
Cu, FSD, 5 cm during second operation
1 Fourteen radon seeds (each Mass regressed. No Age 2 years. Mass
1.4 me, filter 0.3 mm gold) were recurrence at 9-year involved neck and
inserted into substernal mass follow-up mediastinum
extending posterior to the trachea
and downward into the
mediastinum
1 1200 r in 100 r increments over a Progressive reduction of Age 5 weeks. Mass
2-year period the mass involved neck and
Field size: 10 × 10 cm mediastinum
Technical factors: 200 kV, HVL,
0.9 mm Cu, FSD, 50 cm
Hodges et al. 7 50–150 r (125–135 kV) at 4/7 excellent results Age 11 weeks to 11
(1939) 1–2-month intervals to a total years
dose of 600–900 r
8 Pterygium of the Eye ium is surgical removal (Mohammed 2011).

Recurrence after surgical excision is frequent (as
Pterygium is an abnormal growth of epithelial high as 90%) (Fernandes et al. 2005b). Adjuvant
and fibrovascular tissue invading the cornea radiotherapy, using a strontium-90 beta-
across the limbus and can lead to impaired vision irradiation using an eye applicator, has been
or recurrent inflammation (Dushku et al. 2001). shown to decrease vascularization at the opera-
The exact pathogenesis of the disease remains tive site and reduce local recurrences. Such treat-
poorly understood. ment was best administered shortly after excision.
Pterygia are generally asymptomatic and can The North Florida Pterygium Study Group has
be observed with no clinical intervention published that optimal results are obtained when
(Malozhen et al. 2017). In cases of reduced visual radiotherapy is started within 24 h of complete
acuity, induced astigmatism, or frequent inflam- excision (Paryani et al. 1994). However, in recent
mation and discomfort, the treatment for pteryg- decades, there has been a decreasing role of
radiotherapy as the toxicities of radiotherapy able (Fonseca et al. 2018). This is illustrated by a
were more widely recognized and alternative review from Brisbane where the use of beta-
adjuvant therapies, including conjunctival auto- irradiation dropped by 96% between 1990 and
grafts and cyclosporine eye drops, became avail- 2001 (Troutbeck and Hirst 2003).
8.1 Pterygium of the Eye
Number of
Mourits 86 Strontium-90 eye Beta-RT: 5/44 recurrences Mean follow-up of 40
2018 (Qin et applicator post-op: Sham-RT: 32/42 months
al. 2012) 25 Gy to the sclera surface recurrences
(44) vs. sham-RT (42)
Qin et al. 104 (120 Strontium-90 eye No recurrence 10-year follow-up
(2012) eyes) applicator within 6 days
post-op: 20–30 Gy
Viani et al. 200 (216 Strontium-90 eye 3-year LC: Improved cosmetics,
(2012) eyes) applicator post-op: 35 Gy: 94% reduced photophobia,
35 Gy/7 fx vs. 20 Gy/10 fx 20 Gy: 92% irritation, and
within 3 days of surgery scleromalacia in
20 Gy/10 fx
Yamada et 84 (95 eyes) Strontium-90 eye Recurrences: Mean follow-up was
al. (2011) applicator post-op: 40 Gy: 0/28 49.9
40 Gy (28) vs. 20 Gy (67) 20 Gy: 11/67
Nakamatsu 71 (74 eyes) Strontium-90 eye 2-year local: Postoperative RT for
et al. (2011) applicator within 3 days 30 Gy: 85% pterygia is 30 Gy/3
post-op: 40 Gy: 75% fractions considered new
30 Gy/3 fx or 40 Gy/4 fx NS standard
Vastardis et 79 eyes Exclusive strontium-/ No recurrences Median follow-up 46.5
al. (2009) yttrium-90 beta-irradiation, months
dose from 36 to 55 Gy
Viani et al. 623 (737 Strontium-90 eye 73 local pterygium Of the recurrent cases,
(2008) eyes) applicator post-op: recurrences (10%) 80% were noted within
35 Gy/5–7 fx 10-year LC 88% 3 years of treatment
Isohashi et 1147 (1253 Strontium-90 eye 97 local recurrences (8%) Male gender, age <40
al. (2006) eyes) applicator post-op: years, prior treatment,
30 Gy when within 48 h and irradiation <2 h
post-op, 35 Gy for >48 h after surgery were
post-op negative predictors for
local recurrence
Pajic and 43 (54 eyes) Exclusive strontium-/ No recurrence. Reduction Mean follow-up 112
Greiner yttrium-90 beta-irradiation in size in all patients months
(2005) up to a total dose of
50 Gy/4 fx (1 fx/week)
Smith et al. 35 (52 eyes) Strontium-90 eye 1 year LC: 94.6%
(2001) applicator post-op: 25 Gy/5 Recurrences: 5.8
fx
Number of
Willner et 65 (81 eyes) 20 kV X-ray Actuarial 2- and 5-year Mean follow-up 31
al. (2001) Before 1995: 20 Gy in 4 fx recurrence rate is 9% in the months
on mean 4 days following regimen post 1995
surgery. After 1995: 7 Gy compared to 34% and 56%
prior to microsurgical in the historical group
excision, then 5 Gy within
24 h to the surgical bed and
then every other day to a
total dose of 27 Gy
Monteiro- 94 (100 Strontium-90 eye Crude local recurrence
Grillo et al. eyes) applicator post-op: 5.4% in primary group vs.
(2000) Primary (37) 19% in recurrence group.
Recurrent (63) 5-year LC 83.5% for all,
Doses: 94% for primary vs. 77%
30 Gy/3 fx (17) for recurrence
60 Gy/6 fx (80)
20 Gy/1 fx (3)
Nishimura 399 (490 Fractionated RT of In total, 58 (11.8%) local Median follow-up
et al. (2000) eyes) 31–42 Gy/4–5 recurrences of pterygia period was 61 months
fractions/22–29 days was were noted. The median The interval between
given for 95.1% of the time of local recurrences surgery and the start of
pterygia was 10 months, ranging RT (1–3 days vs. >3
452 were fresh, 17 were from 2 to 93 months, and days) and recurrent
recurrences after surgical 16 recurrences (28%) were pterygia were significant
removal alone, and 21 were noted later than 24 months variables for local
recurrences after surgical after treatment control
removal plus postoperative
RT
Fukushima 361 (393 Strontium-90 eye Thirty-four (8.6%) of the Forty-five lesions were
et al. (1999) eyes) applicator: within 48 h 393 lesions recurred. The recurrent cases
post-op 30 Gy, the others overall 1-year local control
received doses of 35 Gy, rate was 93.7%
using the 90Sr eye
applicator
Schultze et 64 Strontium-90 eye 8/64 recurrences (12.5%) Median follow-up 5.5
al. (1996) applicator: 30 Gy/6 fx years
Paryani et 690 (825 90
Sr: 1000 cGy weekly × 6 98.3% control A massive study. Should
al. (1994) eyes) surface dose 6000 cGy 9/14 recurrence had been be reviewed by all
underdosed interested. No
13/14 recurrence, were complications reported
treated with satisfactory
results
Moriarty et 11 selected Sr mean dose 22 Gy.
90
Good review on how to
al. (1993) cases severe Fractionation not manage infection; poor
infection mentioned review of dose
(10,700 fractionation, depth of
cases Rx, Rx
51% scleral
necrosis)
Dasenbury 36 patients 1600–5300 cGy 28% recurrences Calibration
et al. (1992) 90
Sr 2–4 Gy 36% complications uncertainties.
7–27 days Retrospective
undersupplied study.
Good bibliography
Number of
Wilder et al. 338 patients 3 × 800 cGy 85% predictive control 24 h post-surgery
(1992) 90
Sr 10% recurrences
Nowell 205 Excision with immediate 205 treated eyes, 2 Early surgical
(1986) pure beta-irradiation pterygia have recurred intervention. Irradiation
500–1000 r before suturing (1.46% recurrence rate). used as part of the
conjunctiva. Strontium-90 Duration of follow-up 20 primary procedure and
application was used. years not reserved for
Single application recurrences only. No
complications observed
Monselise et 196 (213 Recurrence rate: The difference in the The difference in the
al. (1984) eyes) 10/135 eyes treated with recurrence rate between recurrence rate between
beta rays the eyes submitted to beta the eyes submitted to
22/61 non-treated rays (strontium-90 beta rays (strontium-90
(p < 0.05) applicator) and those not is applicator) and those not
statistically significant. No is statistically
complications. Strontium significant. No
applicator put on the complications.
limbus and sclera at Strontium applicator put
excision site and did not on the limbus and sclera
cover cornea by more than at excision site and did
1–2 mm of its surface. not cover cornea by
Beta-irradiation, thiotepa, more than 1–2 mm of its
and corticosteroid all work surface. Beta-irradiation,
by preventing thiotepa, and
vascularization at operative corticosteroid all work
site, and thus prevent by preventing
recurrence of pterygium vascularization at
operative site, and thus
prevent recurrence of
pterygium
Bahrassa 69 (83 eyes) Excision followed in Thirty-nine percent of Cataract occurred in 5%
and Datta 2–48 h by beta-irradiation nonirradiated eyes suffered of irradiated eyes and
(1983) 1800–2000 r equivalent a recurrence, as compared 10% of nonirradiated
applied to the surgical site with 5% of the irradiated eyes
eyes Lens dose = 70–90 r
Retinal dose = 4–8 r
Alaniz- 483 Surgical excision followed Recurrence rate: 4.32% Radiation within the
Camino by 2800 r in 4–5 days using initial 24 h of surgical
(1982) strontium-90 applicator excision is most
effective in decreasing
recurrence rate
99% of cases involved
the nasal (medial) part
of the eye
Tarr and 57 (63 eyes) Excision followed by Complications: Significant incidence of
Constable beta-irradiation 720–5200 r Scleral ulceration 51 eyes, iatrogenic ocular disease
(1980) (mean 3475) lens opacities 19 eyes, in this series demands a
cataract with reduced need to modify radiation
vision 3 eyes, technique, dose, and
endophthalmitis 4 patients. dosimetry
Also: ptosis,
symblepharon, and iris
atrophy
Number of
Cooper and 403 (526 Excision followed by Recurrences ranged from Results regarding timing
Lerch eyes) beta-irradiation, 1860– 7% to 27%. Patient of irradiation in this
(1980) 3720 r (most 2790 r) in 3 beginning radiation >4 study are at variance
equal fractions over 3 days after surgery had with other series
weeks fewer recurrences than
those irradiated within 3
days of surgery
Pinkerton (975 eyes) Excision and immediate Recurrence rate 6% 20-year follow-up
(1979) strontium-90 application A survey and individual
<3000 r author’s opinion
Rahman et 25 (28 eyes) Excision and beta-radiation Recurrence rate 3.5%
al. (1979) beginning immediately
after surgery. Dose 3750 r
given over 4 weeks in 5
weekly 750 r fractions
Cooper 403 (526 “Bare sclera” excision Recurrence: 32/272 (12%). 50% of the recurrences
(1978) eyes) followed by Sr90 80% of the failures were occurred >1 year after
beta-irradiation salvaged by a second treatment, 25% of these
course of treatment were after 2 years of
treatment
Long-term follow-up is
essential
Ozarda 211 Surgical excision followed Recurrence rate: 1 in 211 No apparent
(1977) by Sr90 beta ray therapy. (<0.5%) complications,
Started within 24 h follow-up of at least 6
postoperatively months
Tong et al. 78 Excision followed by Sr90 8/78 (10%) recurrences 21 (27%) telangiectasis
(1969) treatment beginning 3–4 of the conjunctiva
days post-op 1 showed keratitis (had
3000 reps in 3 fractions at received 5000 reps to
weekly intervals to the two adjacent fields)
surface of the conjunctiva
Cameron 96 Excision immediately Primary cases: Results were just as
(1965, 1968) followed by 2200 r in one 75/83 (93%) satisfactory good with the 9 × 5 mm
application (Sr90) using Recurrent cases: applicator which
9 × 5 mm applicator 10/13 (77%) satisfactory irradiates only
one-fourth of the area
that the 10 mm
applicator does
Therefore, the 9 × 5 mm
applicator is preferred
104 Excision immediately 48/57 (84%) satisfactory; Restriction of irradiation
followed by 2200 r in one recurrent cases: to cut the edge of
application (Si90) using 35/47 (74%) conjunctiva does not
16 mm circular applicator fully inhibit the
regrowth. Therefore, the
bare area should be
included
81 Excision only 8/81 (10%) satisfactory
Number of
28 Excision followed by 17/28 (61%) satisfactory Restriction of irradiation
irradiation restricted to cut to cut the edge of
the edge of conjunctiva conjunctiva does not
only fully inhibit the
regrowth. Therefore, the
bare area should be
included
Rowen 73 Excision followed within 2/27 (7.4%) recurrences A third radiation
(1968) 24 h by 1380 r with Sr90 17/46 (37%) treatment may be given
applicator. Treatment if pterygium is
repeated in 2 weeks especially vascular
Excision only
Von den 1100 Excision followed by 1. 3/7 (43%) recurrences 4/1000 (0.4%) cases of
Brenk irradiation with Sr90 2. 5/39 (13%) recurrences scleral or corneal
(1968) applicator according to one 3. 14/1053 (1.3%) damage (scleral ulcer,
of the following recurrences scleral necrosis, or
techniques: 4. 0/1 recurrences corneal ulcer). All
1. 100 r or 1750 r single occurred with technique
treatment given within 12 h 3
post-op
2. 1800 r, 2000 r, or 3000 r
given in 2 fractions on
post-op days 0 and 7
3. 2400 r, 3000 r, or 3600 r
given in 3 fractions on
post-op days 0, 7, and 14
4. 3200 r given in 4
fractions on post-op days 0,
7, 14, and 21
Duggan 28 Excision followed by 24/25 good results Telangiectasis (1)
(1966) 1000–1200 rep Sr90. 3/3 good results
Radiation only (3 cases):
1. 1000 rep
2. 4800 rep
3. 10,104 rep
Haik et al. 3140 Excision followed 2/3140 (0.6%) recurrences
(1962) and immediately by 900 r (Sr90)
Haik (1966) 249 Excision followed 0/249 recurrences
immediately by 900 r (Sr90)
131 Excision followed 2/131 (1.5%) recurrences
immediately by 900 r
(50 mg radium applicator)
44 Excision only 6/44 (14%) recurrences
Hilgers 83 Excision followed in most 1. 7/33 (21%) recurrences 1. Telangiectasis (1)
(1966) cases within 3 days by 2. 3/18 (17%) recurrences 2. Telangiectasis (1)
irradiation (Sr90): 3. 1/32 (3%) recurrences Irradiation vacuoles (3)
1. 1000–3000 rep Opacities (1)
2. 3000–4000 rep 3. Telangiectasis (3)
3. 5000 rep Irradiation vacuoles (4)
Irradiation dose of 1700 Opacities (2)
rep in one treatment was
never exceeded
Number of
Bernstein 73 Excision followed by 2/46 (6.5%) recurrences
and Unger irradiation of 3000–4000
(1960) rep in 3–5 fractions at
weekly intervals
Excision only 16/27 (59%) recurrences
Lentino et 166 Excision followed in 1 6/166 (3.6) recurrences Telangiectasis of the
al. (1959) week by 2500 reps, Sr90 conjunctiva in 50%.
The majority of patients Keratinization of the
received 2 irradiation conjunctival epithelium
treatments at an interval of (1)
2 weeks for a total of 5000
reps
9 Hemangioma body, they have most commonly been described

in the liver, bones, gastrointestinal tract, and
Hemangiomas are benign vascular tumors, clas- muscles (Yu et al. 2020).
sified as infantile or congenital (DeHart and In rare instances of symptomatic disease,
Richter 2019; Vargis et al. 2017). Hemangiomas management is multidisciplinary and includes
are generally asymptomatic and can be managed surgery, embolization, laser treatment, proprano-
conservatively, but rare symptomatic lesions may lol injection, chemotherapy, corticosteroids, and
be associated with functional impairments, radiotherapy (Vargis et al. 2017). Optimal treat-
bleeding, disfigurement, high-output cardiac fail- ment approach varies based on location, size,
ure, and consumption coagulopathy (Vargis et al. age, histopathological type, and proximity to
2017). While they can occur in any part of the critical structures (DeHart and Richter 2019).
9.1 Head and Neck and Thoracic

Hemangiomas
Total
Author, year cases Treatment Results Notes
Naseripour 21 Ruthenium-106 applicators At 1 year: vision improved in Choroid
et al. (2018) Dose of 30–40 Gy to apex 12 eyes (57%), stable in 7
eyes (33%), and worsened in
2 eyes (10%)
Randon et al. 25 EBRT (20 Gy in 10 Retina reattached at the last Diffuse choroidal
(2018) patients fractions) visit for 24 eyes. Visual acuity hemangioma
(26 stable or better for 20 eyes; 4 Mean follow-up time
eyes) developed mild cataract 47 months
during the follow-up
Papastefanou 60 Observation Any gain in best corrected Choroid
et al. (2018) Photodynamic therapy visual acuity: 80% Mean follow-up, 38–92
(16/60) months
Lens-sparing EBRT (23/60)
Plaque brachytherapy (3/60)
Arepalli et al. 5 Iodine-125 plaque Regression of tumor and Choroid
(2013) Apex dose of 35 Gy complete regression of Mean follow-up of 32
subretinal fluid were months
documented in all cases
Mean tumor thickness
reduction was 37%
Total
Rootman 5 SFRT dose of 40 Gy in 20 fx Resolution of visual field Orbit
et al. (2012) (3), 45.6/28 (1), and defect noted by 3 months Mean follow-up 23.4
49.6/29 Gy (1) Overall tumor shrinkage was months
on average 60% (range:
32–79%)
Kwok- 1 Life-threatening Clinical response was good Mediastinum
Williams thrombocytopenia and Free from progression 4 years Kasabach–Merritt
et al. (2007) consumption coagulopathy. after RT syndrome (huge
No response to steroids and hemangioma with
alpha-interferon thrombocytopenia and
EBRT 9 Gy in 3 fx consumption
coagulopathy)
Aizman et al. 5 Pd ophthalmic plaque
103
All had complete resolution Choroid
(2004) radiotherapy of subretinal fluid with Mean follow-up 18.6
Mean apex dose of 29 Gy reattachment of the retina; months
mean shrinkage 50%
Improvement in visual acuity
(3)
Kivela et al. 5 SFRT 20 Gy in 10 fractions Exudative retinal detachment Choroid
(2003) at median of 5 months
At 20 months: median best
corrected visual acuity 20/50
at diagnosis vs. 20/25 at 20
months; tumor height
decreased by median of 30%
Raja et al. 5 (6 EBRT 21.60 Gy/12 fx Mean baseline visual acuity Retina
(2004) eyes) 20/70 vs. 20/45 at last Mean follow-up 28.3
follow-up months
Mean percentage reduction in
tumor volume was 39.6%
Ogino et al. 13 Median dose of 10 Gy/5 fx Patients with Kasabach– Life- or function-
(2001) Merritt syndrome showed threatening
regression of the hemangioma hemangiomas
and an increase in platelet
counts within 40 days
All but one patient
experienced relief from
symptoms in 40 days
Shields et al. 200 Observation (51%) Complete resolution of Choroid
(2001) Laser photocoagulation subretinal fluid in 60%
(44%) patients at 5 years and 76%
Plaque radiotherapy (4%) patients at 10 years
EBRT (1%)
Surgical repair of retinal
detachment (1%)
Enucleation (1%)
Hesselmann 1 Corticosteroids, interferon Tumor decreased in size and Kasabach–Merritt
et al. (2002) alpha, and radiotherapy coagulation parameters syndrome (huge
9.5 Gy/5 fx normalized within 4 weeks hemangioma with
Platelet counts and thrombocytopenia and
coagulation parameters consumption
normal at 6 months coagulopathy)
Total
Atahan et al. 1 Corticosteroid failed Improvement of both Thigh
(2001) EBRT 9 Gy in 6 fx hemangioma and At 2 years, patient
thrombocytopenia experienced growth
“Dramatic” tumor reduction retardation of the
irradiated leg
Chao et al. 1 Iodine-125 plaque Iris neovascularization Choroid
(2001) 25 Gy to the tumor apex completely resolved at 4
months; improvement of
retinal detachment
At 3 years, complete
resolution of subretinal fluid
and persistent regression of
hemangioma
Zografos 53 (54 RT dose was 27.3 Gy in 4 Retina reattached within 6 48 circumscribed
et al. (1998) eyes) eyes, 22.7 Gy in 3 eyes, and months in all; no recurrence hemangiomas and six
16.4–18.2 Gy in 47 eyes of retinal detachment within diffuse hemangiomas
the follow-up period of 6 in patients
months to 9 years
Madreperla 23 Photocoagulation (13) Brachytherapy: 6/8 had visual Choroid
et al. (1997) Plaque brachytherapy (8) acuity of 6/12 or better at 1
Lens-sparing EBRT (2) year and 8/8 had no subretinal
fluid
Photocoagulation: 5/13 had
visual acuity of 6/12 or better
at 1 year and 6/13 had no
subretinal fluid
Lens-sparing EBRT: 0/2 had
visual acuity of 6/12 or better
at 1 year and 1/2 had no
subretinal fluid
Schilling 36 EBRT (total dose: 20 Gy) Complete resolution of the Choroid
et al. (1996) subretinal fluid (23); residual Mean follow-up 4.5
serous detachment at some years
distance from the fovea (13)
Visual acuity improved by
two or more lines (14);
remained stable (14) or
decreased (8)
Zografos 41 RT Cobalt-60 Retina reattached in all eyes, Choroid
et al. (1996) Dose at apex between 40 and tumor progressively
60 Gy transformed into a flat scar
Rovirosa 1 Not operable Hormonal and visual Maxillary sinus
et al. (1996) EBRT 50 Gy/28 fx functions similar to baseline,
at 2 years
Bek (1980) 5 From 12 to 25 Gy All patients controlled, all Long-term follow-up
hemocoagulation abnormality from 3 to 21 years, no
restored malignancy noted,
thyroid gland continues
to be evaluated
3 Subglottic
2 Liver
Total
Holbrow and 1 2 gold grains (Au 198), Airway had improved greatly Subglottic
Mott (1973) 4 mCi, implanted in the in 2 months Gold grains were
lesion (1 grain was coughed encased in platinum
out 2 days later).
Tracheostomy tube had also
been inserted
Bourne and 1 Nasotracheal intubation and Infant had improved by the Laryngeal
Taylor (1972) prednisone therapy followed next day and nasotracheal
by 500 r (surface dose) with intubation was no longer
beta ray applicator necessary
A second dose of 500 r was
given 8 months later
Calcaterra 1 Tracheostomy: 950 r/5 F/8 No significant regression Subglottic
(1968) days (Co60) through
opposing lateral ports.
Supravoltage irradiation
Tefft (1966) 28 Tracheostomy: 27 patients responded to Subglottic
Initial dose of 100–300 r irradiation but average time 10 cases were
Final dose: for complete regression and irradiated without prior
125 r/2 days to 900 r/12 days relief of respiratory insertion of
Average final dose: symptoms was 9 months tracheostomy tube.
450 r/3 days Authors recommend a
Technical factors: dose of only
200 kV, 15 mA, HVL, approximately 25 r in
2.6 mm Cu such cases
Ferguson and 17 200–500 r/1–6 days 16 lesions regressed promptly Subglottic
Flake (1961) (250–350 r may be given at (6–8 weeks) Tracheostomy was
1 time if the infant has a done in 6 patients
tracheostomy). Technical
factors: 200 kV, 15 mA,
0.4 mm Tn plus 0.25 mm Cu
plus 1 mm Al filtration, HVL
2.7 mm Cu, FSD 50 cm.
Opposing or oblique fields
1 patient received radium
therapy
Holbrow 1 250 r (deep X-ray) to Considerable tracheal Subglottic
(1958) subglottic region obstruction and respiratory
1 month later a second distress following the first
treatment to 200 r was given treatment. Tracheostomy tube
Digoxin, antibiotics, and a was removed after second
third course of irradiation treatment but had to be
were given replaced 2 days later. No
adverse reactions following
the third treatment and the
patient progressed
satisfactorily
1 450 r/2 F/2 weeks No reaction. Stridor ceased 2 Subglottic
days following second
treatment
Baker and 400 r/9 days Response difficult to evaluate Larynx
Pennington Repeated at intervals of 3 1 patient died
(1956) months to a total of 1200 r 1 patient also had extensive
involvement of the
mediastinum which was not
controlled
Total
Kasabach and 1 Tracheostomy: Regression of lesion Subglottic
Donlan 1050 r/7 F/7 days to each
(1945) side of larynx (200 kV,
5 mm Cu plus 1.25 mm Al
filtration, FSD, 50 cm)
1 Tracheostomy: 1000 r/10 F/7 Regression of subglottic Subglottic, lip, anterior
days to each side of larynx lesions. Regression of lip and chest, and nape of neck
(200 kV, 25 mA, 5 mm Cu chest lesion. Regression of
plus 1.25 mm Al filtration, neck lesion
FSD 50 cm). 1500 r/5 F/5
days to lip and to anterior
chest (130 kV, 4 mA, 1 mm
Al filtration, FSD 25 cm).
Radium needles in the nape
of the neck
9.2 Hemangioma of Bone

Total
Yu et al. 6 Definitive SBRT dose 4 (67%) patients reported Vertebral body
(2020) 18 Gy/1 fx (range, 13–20) improvement in presenting
symptoms and 2 patients (33%)
were refractory
Yao et al. 1 EBRT to a total dose of Pain was alleviated, and no Vertebral body
(2019) 40 Gy signs of recurrence at 1 year
Parekh et al. 10 Mean RT dose 47 Gy Actuarial rate of tumor control Mean follow-up 21.2
(2019) was 100% at 5, 10, 20, and 25 years
years Vertebral body
Wang et al. 20 40–50 Gy in 20/25 fx 65.0% (13/20) were symptom Mean follow-up 75
(2018) free, without recurrence or months
malignant transformation at the Vertebral
time of last clinical follow-up hemangioma
(cervical, thoracic,
and lumbar)
Rai et al. 2 Laminectomy, cord Almost complete neurological Mean follow-up 6
(2018) decompression, and post-op recovery in both the cases at months
RT (N/A dose) 6-month follow-up after
surgery
Xiang et al. 1 RT 54 Gy/25 fx Good clinical condition with Hemangioma in
(2017) no recurrence on follow-up cauda equina
MR after 24 months
Zhang et al. 5 (7 SBRT 4/5 patients had improvement Mean follow-up 1
(2017) lesions) in their symptoms (pain or year
weakness) after a mean period
of 1 year
2 had 20–40% reduction in
lesion size
Total
Sewell et al. 1 Radiotherapy with 40 Gy (1 After 1 year, the patient had
(2016) case with spinal cord improved leg strength (MRC
compression and grade 4), was mobilized with
neurological deficits) walking aids for short
distances, and had intact
bladder and bowel function
Cherian et al. 1 Decompressive Excellent clinical recovery at 6 Vertebral
(2014) laminectomy from T4 to months hemangioma
T11, followed by
radiotherapy for residual
tumor
Recurrence 3 years later
with paraparesis and
progressive disease. This
was treated with urgent
radiotherapy. Dose N/A
Jiang et al. 29 RT (10) No recurrence in cases with Mean follow-up 51.1
(2014) Surgery (21) radiotherapy months (range,
3 local recurrence; six cases 24–133 months)
treated by surgical
decompression alone without
radiotherapy
Miszczyk and 101 8–30 Gy in 2–15 Gy/fx Mean pain relief 61%, 65%, Fraction dose
Tukiendorf (137 (111 received 24 Gy in 68%, and 78% at 1, 6, 12, and increase and total
(2012) lesions) 2 Gy/fx) 18 months after RT dose increase
hem 123 had fractionated RT associated with
14 SRS analgesics uptake
reduction and pain
relief
Dang et al. 1 Vertebroplasty, posterior No recurrence was detected by 12-month follow-up
(2012) decompression, and fixation imaging
followed by RT to a dose of
30 Gy
Tarantino 1 RT followed by salvage Patient worsened at the fifth Surgery (T6–T7
et al. (2015) surgery fraction corporectomy with a
Dose of 30 Gy/10 fx titanium expandable
cage implant)
Heyd et al. 84 (96 RT median dose of 34 Gy Overall patient response rate Vertebral
(2010) lesions) was 90.5% hemangioma
Complete symptom remission Median follow-up of
in 61.9%, partial pain relief in 68 months
28.6%, no pain relief in 9.5%
Bellomia et al. 1 Laminectomy, Lower limb tactile sensitivity Vertebral
(2010) embolization, and improved, but paraplegia did hemangioma
radiotherapy not resolve
Aich et al. 7 Radiotherapy (7 patients Pain relief with improvement Vertebral
(2010) with pain and neurological of quality of life in all the hemangiomas
deficits) 40 Gy in 20 fx patients
using Cobalt-60
Total
Grau et al. 1 Radiotherapy 36 Gy in 20 Complete regression of Vertebral
(2009) fx symptoms with stable hemangiomas
condition after 3 months
At the last follow-up, 2.5 years
after treatment—this status
remained stable, the patient
continued to show no
neurologic symptoms
Aksu et al. 1 Radiotherapy Patient’s symptoms improved Vertebral
(2008) significantly hemangiomas
Beyzadeoglu 29 RT total dose 20–30 Gy in Reasonable pain relief was Median follow-up
et al. (2002) 2 Gy/fraction obtained in all 29 patients 14.3 years
Calculated mean
carcinogenesis risk factor is
0.6% for single-irradiation
portals and 0.9% for double-
irradiation portals in the whole
group
Miszczyk 14 RT total dose of 20–30 Gy Complete pain relief in 36% of Vertebral
et al. (2001) cases at 1 month, in 67% at 5 hemangiomas
months. In all remaining cases,
partial pain relief was noted
Sakata et al. 14 RT dose 36 Gy in 18 Pain completely or partially Vertebral
(1997) fractions relieved (13) hemangioma
2 patients with neurological
deficits treated with
decompressive laminectomy
followed by radiotherapy
recovered completely
Winkler et al. 19 RT 20 Gy/10 fx (2) Symptomatic improvement Vertebral
(1996) 30 Gy/15 fx (11) (17) hemangiomas
40 Gy/20 fx (6) Complete remission (7) Median time to
improvement of
symptoms: 3 months
Serrano et al. 1 RT total dose of 37.5 Gy/20 Complete recuperation after 2 Vertebral
(1996) fx (60Co) weeks hemangioma
Patient was disease free at last
checkup
Bremnes et al. 1 Decompressive No recurrence at 2-year Vertebral
(1996) laminectomy and biopsy, follow-up hemangioma
followed by postoperative
RT 40 Gy/20 fx
Schild et al. 13 Orthovoltage and Tumor shrinkage in 9 (82%) of Follow-up ranged
(1991) MV. Doses from 6.25 to 11 cases in which tumor size from 2 to 15 years
40.0 Gy in 1.6–2.5 Gy fx data were collected. Complete (median, 13 years)
response of tumor mass
occurred in 4 (36%) of 11,
partial response in 5 (45%),
and no response in 2 (18%)
Some relief in symptoms in all
13 patients; 10 (77%) had
complete resolution of
symptoms
Total
Asthana et al. 17 RT dose of 35–40 Gy in 3–4 All patients with pain were Vertebral
(1990) weeks using Co-60 relieved completely (87.5%) or hemangioma
partially (12.5%). Out of 9
paraplegic patients, 6 (66.6%)
had recovered completely, 1
(11.2%) partially, and 2
(22.2%) had no response
McAllister 8 1. Surgical removal (2) 1. 1 died post-op Vertebral
et al. (1975) 2. Surgical removal 1 good recovery
followed by radiotherapy 2. Good results
(1) 3. Considerable clinical
3. Decompression followed improvement in both cases
by post-op radiotherapy (2) 4. Lesion was found to be
4. Ligation of feeding filling in with new bone at 5
arteries followed by months post-op. Patient was
radiotherapy (4400 r/3 symptom free at 12 months
weeks) (patient had a 5. Good recovery in both cases
posterior spinal fusion)
5. Radiotherapy alone (2)
Gomez- 1 1000 r/5 F/6 months. Some reduction in tumor size Maxilla
Aravjo et al. Subsequent resection but not complete resolution
(1974) following radiotherapy. Free of
tumor 4 years post-op
Perriman et al. 1 4000 r/1 month. Injection of No regression following Maxilla (central
(1974) sclerosing agent (sodium radiotherapy. Lesion responded cavernous
morrhuate) 6 months later to the sclerosing agent hemangioma)
1 1200 r/4 days (6 MeV) Good response to radiotherapy. Mandible (central
Evidence of bone deposition in cavernous
previously radiolucent areas at hemangioma). Age
3-month follow-up 12 years
Hekster et al. 1 Percutaneous catheter Patient was in excellent Vertebral with spinal
(1972) embolization followed by condition at 7-month follow-up cord compression
radiotherapy (3000 r/12 F/4
weeks, Co60)
Macanash and 1 Short course of radiotherapy Lesion began filling with bone. Mandible
Owen (1972) (dose not stated) Teeth became firmer
Unni et al. 56 Curettage, total excision, or Vertebral lesions: Bone: most were
(1971) resection of as much of the 6/7 good results with located in the skull or
tumor as possible followed decompression followed by vertebra
by radiotherapy in 11 cases, radiotherapy
of which 7 were vertebral
lesions
Loring (1967) 1 1600 r (skin dose)/4 days Swelling flattened, new bones Mandible
(250 kV, HVL 0.5 mm Cu, formed
1 mm Al, FSD 50 cm)
Abramson 1 2700 r/l month (intraoral Regeneration of bone exhibited Mandible
(1965) cone technique) at 6-month follow-up
Topazian 1 3000 r (tumor dose) 15 F/3 No increase in size at 3 months Mandible
(1964) weeks (Co60) (parent’s report). Subsequently
lost to follow-up
Bergstrand 13 Surgery: Laminectomy 8/13 completely cured Vertebral with spinal
et al. (1963) followed by removal (1 4/13 markedly improved cord compression
patient received prior X-ray 1/13 no improvement
therapy but with poor
results)
Total
Rohan (1960) 1 Ligation of left external Pulsation and bleeding in the Mandible
carotid artery. buccal tumor ceased following
Uncontrollable bleeding ligation. Patient was free from
upon extraction of loose recurrences at 8 months
molar and premolar teeth. 3 following radiotherapy
weeks later, 2000 r/2 weeks
to the mandible was given
Smith (1959) 1 2464 r/29 days At 8-month follow-up, the Mandible
facial asymmetry had
disappeared and there was
filling in the active zone of
destruction with new bone
Lindquist 1 Radiotherapy to 5 fields (3 The patient had clinical Vertebral
(1951) dorsal, 2 ventral). Tumor symptoms of compression of Age 18 years
dose of 2100 r. Four series the spinal cord when first
of treatments in 10 months observed. After the last series
were given of treatment, the only
symptoms remaining were
some numbness of the feet and
some insecurity of balance
At 9-year follow-up, mobility
and sensibility were normal
Feber and 1 200 r (air) day to a total of Steady improvement. At Authors report 12
Lampe (1942) 2400 r. Second course 8-month follow-up (after cases in the literature
(2000 r) given 8 months second treatment), patient was similarly treated and
later normal except for areas of also with excellent
Technical factors: 200 kV, minimal hypalgesia in the results
0.5 mm Cu plus 1 mm. Al lower extremities and mildly Vertebral: associated
filtration, HVL 0.9 mm Cu, hyperactive deep tendon with spinal cord
FSD 50 cm, 13 × 15 cm reflexes compression
field Age 52 years
9.3 Liver Hemangiomas

Total
number of
Shimizu 1 Proton beam therapy of One year after proton beam
et al. (2021) 28.6 Gy (RBE) given in 13 therapy, hemangioma had
fractions significantly decreased, and a
complete response has been
maintained for 15 years
based on ultrasound and MRI
Kantor et al. 1 Corticosteroids and Localized hepatic right-lobe
(1999) interferon hypertrophy without
RT 7.5 Gy in 3 fractions functional consequence at 1
using Cobalt-60 year
Partial hepatic
embolization
Total
number of
Biswal et al. 4 RT dose of 30 Gy in 15 fx 3 of 4 cases showed
(1995) complete clinical over a
period of 8–14 months, but
in one case there was only
75% regression of the mass
at 12 months of follow-up
Gaspar et al. 7 RT dose of 15–30 Gy in Improvement of the quality Follow-up ranging from
(1993) 15–22 fx of life in all patients and 40 to 67 months
regression of the tumor
volume were confirmed by
imaging in 5
Corbella Age 4 9.68 Gy At 3-year follow-up, patient –
et al. (1983) months is well
Rotman Age 5 40 Gy Congestive heart failure,
et al. (1980) months corrected
Slovis et al. 3 150–600 r (plus prednisone Tumors regressed but the Two of these patients also
(1975) in 2 cases) role of radiotherapy is had congestive heart
difficult to evaluate failure
Right lobectomy Patient was well at 7-year
follow-up
Ein and 8 Radiotherapy (4) followed Radiotherapy:
Stephens by surgery in some cases 1/4 benefitted. Surgery: 3/6
(1974) died in OR or post-op
McLean 2000 r (6 MeV). Little response to irradiation. Capillary hemangioma
et al. (1972) Prednisone instituted when Dramatic improvement involving the liver
total irradiation had following institution of
reached 1050 r steroids
Kagan et al. 1 5022 r (mid-tumor dose)/2 Marked improvement
(1971) months (daily tumor dose
was increased from 30 r by
increments of 100–114 r
daily, 5 days/week)
Touloukian 1 1050 rads, 2-week course A surgical view of radiation
(1970) prednisone, 2000 rad total and steroids. Look at the
chart
Adam et al. 6 1500–2500 r following Progression of the disease 5 of the patients were 48
(1970) laparotomy was halted in all 6, but 3 years of age or over. 4 of
were not completely relieved the patients had diffuse
of symptoms. Tumor involvement of both lobes
decreased in size in 2
10 Resection (4 lobectomies, 6 2 deaths, both following
wedge resections) emergency resections.
Post-op course
uncomplicated in the other
cases except for 1 who
required drainage of bile in
the subhepatic space
Park and 5 1300–2500 r (tumor Improvement in 4/5 All patients had
Phillips dose/2–4 weeks) 250 kV, undergone prior lobotomy
(1970) 1 MeV, or Co60 and the tumors had been
found to be nonresectable.
4 of the patients were 48
years of age or over
Total
number of
Issa (1968) 2 2500 r (tissue dose)/2 Improvement in both cases
weeks or 2500 r (tissue
dose)/5 weeks
Shockman 1620 r (air)/30 days to each Size of liver decreased. At Cavernous hemangioma
et al. (1963) of the 2 portals for a 3-year follow-up, patient was in both lobes in
calculated midplane dose well and leading a normal widespread distribution
of 2000 r (250 kV, 15 mA, life
Th. II filter HVL 2.3 mm
Cu, FSD 70 cm)
Wilson and 1 700 r/2 weeks (HVL Some decrease in the size of Diffuse cavernous
Tyson 0.95 mm Cu) through 2 the liver. Jaundice hemangioma involving the
(1952) anterior-posterior ports. 3 diminished slightly entire liver
months later, 2700 r/24
days (HVL 2.25 mm Cu)
was given
2 Resection Uneventful recovery
9.4 Cutaneous Hemangiomas
Total
number of Site and age of
Hoehn et 52 Head and Surgery 17/29 (59%) cured Total of 30
al. (1970) neck. Includes 8/20 (27%) significant
both children controlled complications
and adults including:
Radiation atrophy
(4)
Radiation
actinodermatitis (2)
Hemorrhage (post-op
mortality) (1)
Facial nerve
paralysis temporary
(7)
Facial nerve
paralysis permanent
(2)
Delay of wound
healing (4)
Cosmetic defect (10)
4 Radiation 1/4 (25%) cured
(high voltage 2/4 (50%) controlled
or radon seeds)
19 Surgery and 8/19 (42%) cured. 4/19
radiation (21%) controlled
Corby et 1 Cheek Prednisone: no response. Platelet count rose to Associated
al. (1969) Age 3 months 1200 r/4 F normal following thrombocytopenia
radiotherapy.
Hemangioma had
completely regressed
1 year later
Total
Pyesmany 1 Left side of 800 r (300 kV, 20 mA, Following Associated with
et al. neck HVL 2 mm Cu) through irradiation, patient intravascular
(1969) (cavernous) opposed AP ports was asymptomatic coagulation
Age 4 1/2 except for persistent
months petechiae. Patient
completely
asymptomatic at
22-week follow-up
Fost and 6 Face, tongue, Prednisone Marked regression in Regression was
Esterly neck, chest, 5/6 noted within 2 weeks
(1968) and trunk. after beginning
Some had therapy. 3 patients
multiple had regrowth when
hemangiomas. therapy was reduced
All were or discontinued
infants
Zaidi 1 Left temple Prednisone, no Platelet count rose Associated
(1966) Age 7 weeks improvement. following thrombocytopenia
1500 r/8 F/31 days radiotherapy. Tumor
(140 kV, 0.25 mm Cu, had regressed at 2
1 mm Al filter) weeks
Duncan 1 Shoulder 300 r (skin dose) single Lesion responded Associated
and Halnan Age 3 months dose (250 kV, HVL, and platelet count thrombocytopenia
(1964) 1.6 mm Cu, FSD, rose
40 cm)
Chest 375 r (tumor dose) Platelet count fell.
Age not given single dose (300 kV, No response to
HVL, 2.5 mm Cu) betamethasone,
followed by some improvement
betamethasone 2 months following second-
later. Second course of course radiotherapy,
radiotherapy of but platelet count
1500 r/8 F/10 days was remained low
given
Total
Nordberg 1087 Cavernous Contact therapy (for Receiving one The results are at
and hemangiomas minor superficial treatment: 1-year follow-up
Sundberg of the skin. hemangiomas): 50kV, Radium:
(1963) Age not given 0.5 mm Al filtration, <900 r (surface
FSD 20 mm. The dose) (56), 47%
hemangiomas were disappeared. >900 r
compressed during (surface dose) (99),
treatment and the 61% disappeared.
quality of the rays Contact therapy:
modified somewhat (an <900 r (surface
additional 0.5 mm Al dose) (46), 68%
filtration added). The disappeared >900 r
surface dose was 1000 r (surface dose) (262),
for the first treatment 75% disappeared.
and 600–800 r for Receiving two
subsequent treatments treatments:
Radium treatment: Radium:
900–1000 r surface dose <900 r (surface dose
(700–800 r) at 3 mm first treatment) (66),
depth for the first 32% disappeared
treatment. 500–700 r >900 r (surface dose
(3 mm depth) for first treatment) (97),
subsequent treatments 36% disappeared
Contact therapy:
900 r (surface dose,
first treatment) (34),
40% disappeared
900 r (surface dose
first treatment)
(147), 31%
disappeared
Radium and contact
therapy:
30% disappeared
37% disappeared
Sutherland 1 Right ACTH and prednisone. Platelet count rose. Associated
and Clark submandibular 675 r (air)/7 F/3 weeks Hemangioma had thrombocytopenia
(1962) and anterior regressed markedly
cervical at 1-month follow-up
Age 3 months
9.5 Hemangioma of the GI Tract

Total
number
of Site and age
Author, year patients of patients Treatment Results Notes
Allred and 40 Colon, Treatment: Failures: If complete
Spencer rectum, Local removal 1/13 removal of the
(1974) and anus. Radical hemorrhoidectomy 0/2 hemangioma is not
Average Resection 0/4 feasible, treatment
age 45.7 Radiation 0/2 is directed at
years Oral iron 1/6 relieving the
Transfusion 0/2 symptoms
Abrahamson 8 Bowel Radium therapy 2/3 cured
and Shandling Excision 5/5 cured
(1973)
Oppenheim 2 Rectum Radium pack to the anterior Good results in both
and O’Brien pelvis and sacrum (1). 200 r cases. No
(1950) (skin dose) daily to a total of recurrences of
2552 r tumor dose (200 kV, gastrointestinal
HVL, 9 mm Cu, FSD 80 cm, complaints or
20 × 20 cm field) bleeding
9.6 Hemangioma of the Urinary Tract

Author, Total number of Site and age of
Liang 2 Bladder 250 r (air)/10 F through an Good results in
(1958) Ages 52 and 64 anterior port both cases
years
9.7 Hemangioma of the Joint

Total
Author, number of
year patients Site Treatment Results Notes
Moon 133 Knee 1. Radiotherapy 1. 8 recovered, 1 The cases listed consist of 2
(1973) joint (10) functional limitation, 1 cases reported by Moon plus
2. Synovectomy residual tumor cases provided in a review of
(11) 2. 8 recovered, 2 the literature reported in
3. Partial recurrences Moon’s paper
synovectomy (19) 3. 13 (76%) recovered, 3
4. Mass excised functional limitation, 1
(86) recurrence
5. Partial excision 4. 56 (73%) recovered, 19
(7) functional limitation, 2
residual tumor
5. 2 (29%) recovered, 4
residual tumor, 1
gangrene—amputation
later performed
9.8 Intracranial Angiomas

Total
number
of
Xin et al. 54 RT 50 Gy in 25 fx Tumor shrinkage within 3 months Cavernous sinus
(2020) Mean tumor reduction of 79.7% (range, hemangioma
48.4–98.5%) with no patients
experiencing tumor progression and
recurrence
All patients experienced symptomatic
improvement within 1 month to 12
months
Lichao 12 CK SBRT Tumor volume reduction from 29% to Mean follow-up
Huang et al. 19.5 Gy/3 fx (2) 94%, symptoms improved (including 16.3 months
(2019) 21 Gy/3 fx (8) blurred vision, visual field defects, Cavernous sinus
25 Gy/5 fx (1) diplopia, headaches, and facial
3 Gy/3 fx (1) numbness) in all
Tang et al. 53 Mean marginal dose of Tumor control rate of 100%. Mean Mean radiological
(2015) 13.3 Gy (range, tumor volume reduction was 79.5% and clinical
8–15 Gy) to the (range, 16.5–100%) compared with the follow-up time of
49–64% isodose line pre-GKS volume this study was 24
(mean 53%) and 34 months,
respectively
Song et al. 19 SRS median marginal Average tumor volume had decreased to Mean follow-up
(2014) dose at the 50% 26% (range, 0–70%) of the initial period was 37
isodose line was volume at the last follow-up MRI months
14.5 Gy (range,
11.5–16.0 Gy)
Morace 4 Partial resection, No local recurrence Intracranial capillary
et al. (2012) followed by hemangiomas
radiotherapy (2)
Subtotal resection after
embolization, then
salvage RT at 1 year
(1)
Surgery only (1)
Wang et al. 14 SBRT 21 Gy in 3 fx MRI showed mean 77% tumor volume Mean follow-up of
(2012) reduction. Among the 6 patients with 15 months
cranial nerve impairments, 1 had
symptomatic complete resolution and 5
had improvement
Yamamoto 30 Mean dose to the tumor Among the 22 patients with symptoms Mean follow-up
et al. (2010) periphery was 13.8 Gy prior to GKS, complete remission was period was 53
(range 10.0–17.0 Gy) achieved in 2, improvement in 13, and months
no change in 7. Hemifacial sensory
disturbance developed following GKS
in 1 patient. The most recent MR
images showed remarkable shrinkage in
18, shrinkage in 11, and no change in 1
patient
Park et al. 10 Fractionated RT total Average tumor volume reduction was Median follow-up
(2017) dose of 50–54 Gy in 72.9% (range, 18.9–95.3%). All 10 of 6.8 years
25–27 fx the cranial neuropathies improved, with
complete symptomatic remission in 9
cases (90%) and partial remission in 1
case (10%)
Total
number
of
Grosu and 1 Postoperative SFRT to Symptomatic improvement at 6 months Cavernous sinus
Nieder residual tumor 40 Gy Imaging over a 20-month period
(2006) in 20 fx showed a continuous and pronounced
decrease in residual tumor size
Tsao et al. 2 SFRT 45 Gy/25 fx (1) Symptomatic relief Cavernous sinus
(2003) SFRT 50 Gy/25 fx (1) Complete remission (1)
Minor residual contrast enhancement
without progression (1)
Jamjoom 1 EBRT 50 Gy/25 fx Improvement in visual symptoms and Cavernous sinus
(1996) reduction in size on imaging at
13-month follow-up
Zeller and 1 3000 r/4 weeks to the Patient died 2 months later Pons
Chutorian pons
(1975)
Paterson and 108 1. Total excision (36) 1. 1 Post-op death. 2 late deaths from Intracranial
McKissock 2. Ligation of the intracerebral hemorrhage, 3 are
(1956) cortical vessels alone incapacitated. 29 alive and doing
(15) full-time work. 1 lost to follow-up
3. Ligation of the 2. 11 working full-time. 3 incapacitated.
common carotid artery 1 too recent to assess results. 1 lost to
alone (4) follow-up
4. Radiotherapy alone 3. 2 no effect, 1 transient relief of
(6) or following headaches, symptoms worse at 1-year
surgery (5) follow-up. 1 died 24 h post-op (was in
5. No treatment (42) deep coma pre-op)
4. No benefit in any case
5. 3 deaths just after diagnosis. 5
hemorrhages. 1 death at 7 years. 14
well at the end of follow-up with no
serious disabilities. 1 remained
hemiplegic. All others lost to follow-up
Potter 45 Treatment: Survival after Rx in years Cerebral
(1955) Symptomatic 0–5 5– 10–
radiotherapy radical 10 20
excision 28 7 3 –
2 1 3 4
6 1 – –
– –
Bergman Total of 1750 r (air) Recurrent attacks of bulbar palsy Pons
(1950) over a period of 5 years responded to radiotherapy. Patient died
given in the courses of approximately 5 years after first
approximately treatment
750–1800 r to each of
the 3 or 4 portals
10 Inverted Papilloma Median age at presentation is 55 years and affects

males more frequently (3:1 ratio) vs. females
Inverted papilloma is a rare locally aggressive (Vrabec 1994). The most common symptom at
neoplasm of the sinonasal mucosa characterized presentation is nasal obstruction, but other symp-
histologically by squamous metaplasia expanding toms may include facial pain or pressure, epi-
inward toward the stroma (Karkos et al. 2006). staxis, headaches, and epiphora (Vrabec 1994).
Inverted papilloma may transform into or be inverted papilloma without malignant transfor-
associated with a squamous cell carcinoma in up mation, radiotherapy has been used anecdotally
to 15% of cases. in unresectable or multiply recurrent disease.
The treatment of choice for inverted papil- Radiation doses between 50 and 60 Gy have
loma is wide excision, which can be open or been typically used after gross or subtotal resec-
endoscopic and is associated with a 10–20% tion, whereas doses in the range of 70 Gy have
local recurrence rate (Strojan et al. 2012; been proposed in large unresectable disease
Attlmayr et al. 2017). In the context of benign (Strojan et al. 2013).
10.1 Inverted Papilloma

Total
number
of
Author, year patients Site and age Treatment Results Notes
Nath and 1 Middle ear and Post-op Local recurrence at 11
Das (2016) mastoid, 60 years Cobalt-60 EBRT months posttreatment
54 Gy/30 fx
Rutenberg 2 Sinonasal 1. Definitive EBRT 1. Complete response;
et al. (2013) Median age 53 65 Gy in 36 fx died at 8 years of
years 2. Open surgery intercurrent disease
followed by EBRT 2. No recurrence; died
65 Gy in 36 fx split of intercurrent disease
course at 9 years
Strojan 1 Sphenoid and Adjuvant EBRT No recurrence at 2.6 No deterioration
et al. (2013) adjacent 54 Gy/30 fractions years of olfaction,
cavernous sinus; hearing or vision
69 years
Kainuma 1 Middle ear; 63 Gross tumor resection No recurrence at 0.8
et al. (2011) years followed by year
EBRT54 Gy/30 fx
Gomez 5 Nasal cavity or 1. Str + RT 47.15/32 NED at No patient
et al. (2000) paranasal 2. Gtr + RT 67 Gy in 1.4–20.5 years developed a
sinuses; age 60 fx BID malignant
32–84 years 3. Gtr + 61.3 Gy in 32 transformation
fx
4. Gtr + 60 Gy en 33
fx
5. Definitive 65 Gy in
36 fx
Miller et al. 1 Frontal sinus, Gtr followed by RT to NED at 3 years Intracranial
(1996) intracranial 70 Gy extension and
extension; 42 dural penetration
years
Hug et al. 7 Sinonasal, 3 patients: 1 STR had local Median follow-up
(1993) nasopharynx; age GTR + adjuvant RT recurrent successfully time 0.5–12.9
30–70 years 51.2–56.6 Gy treated with repeat years
3 patients: surgery, remained
STR + adjuvant RT NED at 5.2 years
56.4–64.8 Gy BID
Dolgin 41 Nose and All underwent surgical Recurrence rates were Authors
et al. (1992) paranasal sinuses excisions 22-29% recommend XRT
Ages: 11-78 5 (12%) had inverting if malignancy is
years (mean 61 papilloma with present
years) squamous cell
carcinoma
Total
number
of
Author, year patients Site and age Treatment Results Notes
Guedea 7 Nasal cavity and 1: XRT alone 6 of 7: disease free,
et al. (1991) paranasal sinuses 2: XRT plus resection 4–20 years after XRT
Ages: 40–84 Doses: 47–69 Gy in 1: local recurrence
years 180 cGy fractions
Levendag 1 Nasal cavity and Extensive surgery with Patient controlled with Inverted
et al. (1984) paranasal sinuses residual disease, radiotherapy; NED at papilloma with in
followed by 1-year follow-up situ carcinoma
postoperative
radiotherapy
Total dose 64 Gy
Fechner and 1 Medial canthus Resection of neck PD locally at 1.8
Sessions and right neck mass and medial years, NED at 3 years
(1977) mass, 22 years maxillectomy after surgery
old 50 Gy
11 Neurofibroma may catch on clothing and cause cosmetic issues,

stinging, or itching. Such symptoms as well as
A neurofibroma is a benign nerve sheath tumor of growth concerning for malignant transformation
the peripheral nervous system, arising from may motivate surgical removal. Radiotherapy has
myelinating-type Schwann cells (Lott and been used parsimoniously for recurrences or in
Richardson Jr. 1981). Neurofibromas are most situations where surgery would be excessively
often sporadic but are obviously common in morbid. There is a trend toward using less radia-
those individuals known for neurofibromatosis tion in patients with neurofibromatosis, and
(NF1 or NF2). recently there have been promising reports of
Most neurofibromas associated with neurofi- neurofibromas durably responding to MEK
bromatosis will not require any treatments. They inhibitors (Dombi et al. 2016).
Total
Robertson 1 EBRT standard fractionation to Tumor size reduction and no Solitary plexiform
et al. (2004) 60 Gy recurrence at 3 years post-RT neurofibroma of the
tongue base
Wentworth 6 SRS (median dose, 1200 cGy; Five-year PFS rate 100% Schwannoma/
et al. (2009) range, 1000–2400 cGy) neurofibroma
Median follow-up
48 months
Chopra 4 RT 50–54 Gy/30 fx (3) LC 100%; 1 died of intercurrent Followed from 1.7
et al. (2005) SRS 12.5 Gy/1 fx (1) disease; 3 had no disease to 14.8 years
progression at the last follow-up
Tepper and 8 Radiation therapy 6400– 100% actuarial local control and
Suit (1985) 6600 cGy in shrinking field survival at 5 years
technique
Smalley 1 Surgical excision, postoperative Relief of discomfort. Developed (L) sciatic nerve
et al. (1984) radiation of 4500 r to pelvis, metastatic disease 10 months after
540 r sacral boost, 1000 r radiation; treated with
intraoperative radiation to (L) chemotherapy. 20 months after
pelvic sidewall plus 500 r boost irradiation, while on
chemotherapy, had apparent local
control
Total
Greenberg 3 4800–6400 r one patient Two out of three controlled Supraclavicular, hip
et al. (1981) hyperfractionated neck
5500 r or more
based on limiting
tissue
Suit and 1 Surgical resection and Free of tumor and asymptomatic at Right, premaxillary
Russell postoperative radiation, 4600 r 2 years posttreatment space; 12 years old
(1975) external beam followed by
2600 r radium needle implant,
total 7200 r
12 Plasma Cell Granuloma/ neck. In the head and neck, the orbit and paranasal
Inflammatory Pseudotumor sinuses are the most frequently involved subsites.
Inflammatory pseudotumors are most common in
Plasma cell granulomas (also called inflammatory patients younger than 30 years.
pseudotumors) are rare benign inflammatory The treatment of choice is complete surgical
tumors formed by fibrous connective tissue infil- removal. However, in rare circumstances where
trated by plasma cells and other inflammatory the lesion cannot be resected without significant
cells. Inflammatory pseudotumors most frequently morbidity, radiotherapy may have a role.
occur in the lung but have also been reported in the Radiation doses between 40 Gy in 20 fractions
gastrointestinal tract, urinary system. or head and and 50.4 Gy in 28 fractions have been reported.
Total
number of
Author, year patients Method Results Comments
Ajibade 1 Definitive excision with Disease free at Temporal bone
et al. postoperative steroids and last follow-up
(2010) radiotherapy
Strasnick 2 Adjuvant RT total of 20 Gy No tumor Temporal bone
and in 10 fx; steroids during RT recurrence by
Vaughan and then tapered MRI imaging at 8
(2008) years and 10
years
Lee et al. 8 Steroids only (2) 1/8 had stable Skull base (5)
(2006) Steroids + RT (6) condition without Cervical vertebral body (1)
RT dose to the skull-base neurologic
lesions 2000 cGy symptoms
One patient had reRT of Patients receiving
3000 cGy to the cervical RT showed either
vertebral bodies symptomatic
recurrence or
residual disease
Janicki 1 Mastoidectomy and RT Persistent mass; Mastoid, middle ear, posterior fossa
et al. 50.4 Gy in 28 fx no increase in dura, and petrous apex
(1996) size on MRI at 12
months
Newlin 1 45 Gy in 25 fractions, Disease free 8 Maxillary sinus
et al. experienced a local years after initial
(2005) recurrence 2 years later. treatment
Resection, followed by
another recurrence, treated
with SRS
Total
number of
Nam et al. 1 Mastoidectomy and RT to a No evidence of
(1994) dose of 50.4 Gy in 28 fx disease at 1 year
Benton 1 Craniotomy, radical No evidence of Middle ear and mastoid
et al. mastoidectomy, and disease on
(1992) radiotherapy physical
examination and
MRI at 1 year
Seider 1 Recurrence 1 month Free of Nasal cavity
et al. post-gross macroscopic recurrence at 27
(1991) resection treated with months
definitive cobalt-60 RT to a
dose of 40 Gy in 20 fx
Lanciano 23 (26 20 Gy in 10 77% of orbits had Median follow-up was 41 months
et al. orbits) fractions ± steroids durable local Orbital pseudotumor
(1990) control and were
steroid
independent
Imperato 2 Uncomplete resection lung Free of Case 1: partial resection unresected
et al. plasma cell granuloma recurrence for 11 portion of the tumor involved the
(1986) 4320 rad in 4.5 weeks and years and 5 years septum between the right and left
4500 rads in 4.5 weeks atrium, constriction of the
esophagus
Case 2: first complete resection,
followed by recurrence 4 years later.
He underwent thoracotomy on
March 20, 1981, at which time the
tumor was wrapped around the
descending aorta and had invaded
the mediastinum and left hilum. The
lesion could not be resected
Mehta 1, 4 MeV, 2 courses Was not equivalent to Hoover and
et al. 71-year- 200 × 9 = 1800 cGy was an older patient and
(1980) old male 300 × 10 = 3000 cGy endobronchial
Hoover One 4 MeV Complete Partially resected and grew. Then
(1977) 15-year- 19 Fxs resolution radiation followed by complete
old male 4040 rads resection would have required a
pneumonectomy
13 Pineocytoma Historically, the preferred treatment approach

is gross tumor resection, which has been reported
Pineocytomas are benign slow-growing tumors to provide a survival advantage compared to sub-
derived from the pineal epithelium, representing total resection (Clark et al. 2010a). The benefit of
12% of all pineal tumors and most often occurring adjuvant radiotherapy after subtotal resection is
in adults aged between 30 and 60 years (Clark et al. not (Clark et al. 2010b). More recently, stereotac-
2011). While small pineocytomas are typically tic radiosurgery has emerged as an effective ther-
asymptomatic, larger tumors may induce head- apy achieving a local control of 81% at 20 years
aches, obstructive hydrocephalus, visual impair- (Lekovic et al. 2007; Reyns et al. 2006; Mathieu
ment, or Parinaud syndrome (Favero et al. 2021). and Iorio-Morin 2019).
Total
number of
Iorio- 26 Median prescription Actuarial local control and
Morin dose was 15 Gy at the survival rates were 81% and 76%
et al. 50% isodose line at 20 years for pineocytoma
(2017)
Lekovic 8 GK SRS Partial response or no change at
et al. Prescription dose at 50% 2–56 months posttreatment
(2007) isodose line (Gy)
13–16 Gy
Reyns 8 GK SRS All tumors responded to treatment Mean follow-up of 34
et al. Marginal dose to these and disappeared or ceased months (range 6 to 88)
(2006) tumors ranged from 11 growing
to 20 Gy (mean 15 Gy)
Clark 166 1. 20% biopsy 5-year PFS for resection group vs. No significant difference
et al. 2. 38% STR biopsy: 89 and 75% (p < 0.05) in PFS for STR only
(2010b) 3. 42% GTR 5-year PFS GTR vs. STR + RT compared with STR in
4. 28% RT 100 and 84% (5 years) (p < 0.05) addition to radiation
therapy
Sakoda 2 1. 45 years old: RT 1. CR at 3 months, no recurrence
et al. 5000 rads at 1 year
(1989) 2. 6 years old: four 2. CR and no recurrence at 18
cycles of intravenous months
infusion of ACNU
(25 mg) over 10 months
Allred HW, Spencer RJ (1974) Hemangiomas of the

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Vascular Disorders
Luis Souhami
Contents 1 Arteriovenous
1 Arteriovenous Malformations (Brain) 295 Malformations (Brain)
2 Cavernous Angiomas (Brain) 300
Brain arteriovenous malformations (AVMs) are
3 Coronary and Peripheral Arterial abnormal, direct arteriovenous shunting con-
Stenosis 303
taining a cluster of pathologically dilated arter-
4 Dural Arteriovenous Fistulas (Brain) 309 ies and veins forming a vascular nidus.
5 Hereditary Hemorrhagic Telangiectasia Intracranial hemorrhage is the major source of
(Osler-Weber-Rendu Syndrome) 313 morbidity and mortality. The annual risk of
References 317 hemorrhage may range from 1% for unrup-
tured, superficially located and with superficial
drainage AVMs to close to 35% for previously
ruptured, deeply seated and with deep venous
drainage AVMs. The Spetzler-Martin scale,
based on nidus size, AVM location, and pres-
ence of deep venous drainage, is commonly
used to grade the AVM. Treatment options
include observation, surgery, embolization,
conventional radiotherapy/stereotactic radio-
surgery (SRS), or a combination of these treat-
ments. SRS became an attractive treatment
alternative for small (≤3 cm), deep-seated
lesions. SRS can be delivered by the gamma
knife, protons, or linear accelerators (linac).
The goal of SRS treatment is to achieve a com-
plete obliteration of the AVM, which can range
from 20% to 100%, by delivering a high radia-
tion dose to the AVM while minimizing expo-
sure to the surrounding normal brain. However,
L. Souhami (*)
Division of Radiation Oncology, Department of the latency period between SRS and complete
Oncology, McGill University, Montreal, QC, Canada obliteration ranges from 1 to 5 years. There is a
e-mail: luis.souhami@mcgill.ca close margin of safety relative to total dose

296 L. Souhami
delivered and treatment volume. The series excessive complications. The use of conven-
reported to date document shrinkage of AVMs tionally fractionated radiotherapy has been
and partial to complete obliteration of lesions reported in a small number of patients and with
with associated symptomatic relief without limited results.
Total #
Author, year patients Age (years) Treatment Results Notes
Mohr et al. 57 Mean: Multicentric, randomized Mean follow-up: Only randomized trial
(2020) 44.4 study comparing 50.4 months. Medical comparing observation
(ARUBA observation (medical management alone was vs. treatment for
trial) management) vs. superior than treatment unruptured AVMs.
interventional therapy for the primary outcome Trial criticized for
(surgery or embolization selection bias,
or SRS) in adult patients questionable treatment
with unruptured AVMs. choices (only 16%
Primary endpoint was underwent surgical
time to death or excision), and
symptomatic stroke. Trial inadequate quality
was closed prematurely control
after interim analysis
(226 of a planned 400
patients)
Chen et al. 1258 Mean: Gamma knife SRS. Mean Mean follow-up: This retrospective
(2021) 38.9 margin dose to prior 64.8 months. Crude AVM multicentric study
embolization plus SRS obliteration rates were shows that previous
was 18.9 Gy and it was similar between the embolization does not
21 Gy for SRS alone matched endovascular lead to worse outcome
embolization + SRS vs. after subsequent SRS
SRS alone. Rates of
complication and
post-SRS hemorrhage
also similar between
cohorts
Frager 121 Median: Linac based. Median Median follow-up: Retrospective study
et al. 37.7 dose: 18 Gy 88 months. Complete comparing outcomes
(2020) obliteration rate: 63%. of patients treated with
No difference between frame-based vs.
frame-based vs. frameless SRS.
frameless SRS 3-dimensional
rotational angiography
used to treat frameless
SRS
Chen et al. 539 Mean: 13 Mean margin dose: 153 patients with A retrospective
(2019) 19.9 Gy unruptured and 386 with multicenter study with
ruptured a pediatric cohort
AVM. Obliteration rates
were similar between the
two groups. Risk of
post-SRS hemorrhage
increased in ruptured
AVM, but complications
more frequent in
unruptured AVMs
Vascular Disorders 297
(continued)
Total #
Cohen- 2231 Median: All treated by gamma Early obliteration A retrospective review
Inbar et al. 36.2 knife. A complete (<18 months) was more from 8 active medical
(2017) obliteration rate of common in patients with centers worldwide
62.6%. Early smaller AVM nidus, with experience in the
(<18 months) vs. late which had deep venous management of AVMs
responders (>18 months) drainage, received margin
studied dose >24 Gy, and was in
the frontal lobe, basal
ganglia, or cerebellum.
Early obliteration was
also more common in
patients without prior
radiotherapy or prior
subtotal microsurgical
resection
Starke 2236 Mean: 36 SRS delivered by gamma Total obliteration seen in Predictors of complete
et al. knife. The mean AVM 64.7%. Annual obliteration were AVM
(2017a, b) maximum diameter was hemorrhage risk was volume, higher SRS
2.3 cm, and the mean 1.1%. 29% of patients dose, and non-
volume was 4.3 cc. developed complications, eloquent location
Median dose to the AVM but symptomatic in only
margin was 20.5 Gy 9.7% and with permanent
disability in 2.7%
Starke 357 Mean: All treated by gamma Mean follow-up was Large pediatric cohort
et al. 12.6 knife. Mean nidus 92.4 months. Complete from an international
(2017a, b) volume was 3.5 cc. Mean obliteration of 63.3%. In consortium
dose (at the periphery) 41 patients, obliteration
was 21 Gy (range: 5–35). verified by MRI only
The Martin-Spetzler
grade was III to V in
58.8% of patients
Ding et al. 565 Median: Gamma knife SRS. Dose: Obliteration rate for All treated patients
(2014) 28.8 22 Gy prescribed to the cohort with 2 years of with ruptured AVMs
50% isodose surface follow-up: 76%. prior to SRS. Results
Actuarial obliteration similar to unruptured
rates of 41% and 64% at AVMs. Pre-SRS
3 and 5 years, embolization
respectively associated with worse
outcome
Flickinger 351 Median: Gamma knife. Median 3-year minimum A dose-response curve
et al. 34 marginal dose 20 Gy follow-up. Angiographic is described by the
(2002) (range: 12–30). Median obliteration of 73% authors. No benefit for
volume: 5.7 cm3 (193/264 patients doses beyond 23 Gy
studied)
Schlienger 169 Median: Linac-based SRS. Follow-up ranged from Treatments well-
et al. 33 15 MV. SRS alone in 48 to 96 months. tolerated. One large
(2000) 55% of patients. Dose: Complete obliteration series of Linac-based
25 Gy to periphery of rate was 64% SRS from France.
AVM
Karlsson 945 Median: Gamma knife. Patients An 82% obliteration rate.
et al. 28 treated between 1970 and The mean dose in
(1997) 1990. Original dose was obliterated cases was
50 Gy to the isocenter 37 Gy, while it was
(25 Gy marginal dose) 29 Gy in non-obliterated
cases (p < 0.0001)
(continued)
298 L. Souhami
(continued)
Total #
Friedman 158 Mean: 39 Linac-based SRS. Mean Mean follow-up of Authors report a
et al. dose 15.6 Gy (range: 33 months. 80% relationship between
(1995) 10–25) prescribed to the angiographic cure (48/60 volume of the AVM
80% isodose surface patients studied at 2 years and the outcome
or more) post-SRS
Lunsford 227 Mean: 33 Mean dose to AVM 46 patients with repeat 2 patients developed
et al. margin 21.2 Gy (range: angiogram at 2 years. permanent
(1991) 12–27). In 98% dose Complete obliteration in neurological deficit
prescribed to the 50% 37 (80%). Obliteration First gamma knife
isodose surface was size dependent used in the United
States
Souhami 25 Median: Dose: 20–25 Gy 14 patients had repeat First Linac-based SRS
et al. 26 delivered to the periphery angiogram at 1 year. 6 report in Canada
(1990) of the nidus. Single patients (43%) achieved
fraction complete obliteration and
3 others had more than
75% decrease. Two late
complications
Spry et al. 33 Median: Dose: 30–50 Gy Median follow-up of Fractionated
(1990) 35 (Median dose: 46 Gy) 79 months. Only 7 radiotherapy delivered
fraction size ranged patients had follow-up by Cobalt-50 or 4 MV
between 1.5 and 3.0 Gy angiogram. One complete Linac. Old techniques
obliteration. Doses above used
45 Gy appeared to be
associated with less
bleeding
Alschuler 18 Mean: First treatment delivered 7 patients with follow-up First report of SRS
et al. 12.3 in August 1987 angiogram at 1 year. 3 using gamma knife in
(1989) Pediatric population patients with complete the United States
obliteration
Kemeny 180 Mean: All treated on the gamma Only 52 patients followed First gamma knife
et al. 29.7 knife. Dose: 25 Gy/single for 1 year or more. 16 SRS report in the
(1989) session. Dose prescribed patients (31%) achieved a United Kingdom
to the periphery of the complete obliteration and
AVM another 10 (19%) had a
major change in the AVM
Loeffler 16 Median: Dose: 15–25 Gy/single 11 patients followed No complications
et al. 22 session. Dose prescribed more than 1 year. reported.
(1989) to the 80–90% isodose Complete obliteration in First Linac-based SRS
surface 5/11 patients (45.5%) at report in the United
1-year and 8/11 (72.7%) States
at 2-year follow-up
Colombo 45 Range: Dose: 20–40 Gy 10 patients had DSA at No complications
et al. 10–62 Single session in 41 12 months. Two with reported. First
(1987) patients and 2 sessions in complete obliteration and Linac-based SRS
4 6 with major changes in report from Europe
AVM
Poulsen 6 Median: 45–75 Gy/20 1/6 had complete clearing Hypofractionated
(1987) 23.5 fractions/4 weeks using of AVM radiotherapy. No
4 MV linear accelerator None had recurrent treatment
bleeding. Two patients complications
with previous partial Minimum follow-up
surgical removal 17 months
(continued)
Total #
Betti et al. 186 Not Linac 10 MV. Doses First 58 treated patients: First Linac-based SRS
(1989) available ranged from 20 to 70 Gy. complete obliteration in in the world. First
80% of patients received 82%. Obliteration was patient treated in 1982
less than 40 Gy size dependent. One (in Argentina)
(Neurosurgery patient developed
1989;24:311) temporary brain edema
Makkoski 79 Median: Linear accelerator 25 patients with No complications
et al. 35 10 MV. Therapy in a follow-up achieved a reported
(1986) semi-stereotactic fashion reduction of more than
Doses: 50 Gy in 25 50% of the volume of the
fractions or 20 Gy in 4 AVM. In 3/25, the AVM
fractions was completely
obliterated
Spetzler A grading system for Grading system used
and Martin AVMs by most authors
(1986)
Tognetti 1 27 Conventional irradiation. DSA done 2 years Conventional
et al. Dose: 4500 rads, posttreatment showed fractionation
(1985) delivered in 6 weeks, only minor residual nidus
150 rads daily, 5
treatments weekly
Fabrikant 130 Not Radiosurgery Bragg peak Complete obliteration in Follow-up is short
et al. available helium ions 6 of 33 patients (18%) (update of Fabrikant
(1985) Maximum range of the and partial in 60% with 1984 paper)
helium-ion beam is angiographic follow-up.
230 MeV/u. Total doses: Clinical symptoms:
25, 35, or 45 Gy 68% improved
equivalent to volumes neurologically, 24% no
120–25,000 mm3 via 3–5 change, 7% worsened
entry portals
Kjellberg 75 Mean: 31 Stereotactic Bragg peak 62 patients had follow-up Follow-up on 244 of
et al. proton therapy. 11% angiography. 439 patients (55%).
(1983a, b) complication rate. Hemorrhage rate = 2.4%/ Complication was
Dose-volume relationship year. Seizures improved amplified by
established in one-half. 1/3 had subsequent letters to
neurologic deficit the editors in the
improved NEJM
2/3 had lessening of
headaches. 87% had
reduction of AVM
Leksell 204 Not Original gamma knife Total obliteration in A review article
(1983) available unit 83.5% of cases, partial
obliteration in 10.5%,
and no change in 6%
after 2-year follow-up of
67 patients
Steiner 5 Not Original gamma knife Dose delivered: 2 patients: complete
et al. available. unit 5000 rads obliteration
(1974) One
pediatric
patient
Steiner 1 69 Original gamma knife Only feeding arteries First patient treated on
et al. unit. Treated in 1970 targeted. Complete the gamma knife
(1972) 5000 rads delivered to the obliteration at 21 months
50% isodose post-SRS
(continued)
300 L. Souhami
2 Cavernous Angiomas (Brain) those whose lesions showed a previous hemor-

rhage. They are sporadic in 80% of patients.
Cavernous angiomas (also referred to as cavern- Familial cases represent 20% of all cavernomas
ous malformations, cavernous hemangiomas, or and have an autosomal dominant inheritance pat-
cavernomas) are benign, low-flow angiographi- tern. In approximately 10% of patients with the
cally occult vascular malformations occurring in sporadic form, the vascular lesion can be multi-
any region of the brain. They are composed of ple while multiple cavernous angioma is a com-
endothelial-lined sinusoidal collections lacking mon feature in the familial form. There is a
smooth muscle and that are devoid of intervening similar prevalence in women and men. The treat-
brain parenchyma. They represent 10–15% of all ment of choice is a microsurgical removal. The
brain vascular malformations. There are reports use of radiotherapy/radiosurgery (SRS) remains
of these lesions developing years after radiother- controversial. Several reports suggest a decrease
apy. The introduction of MRI has increased the in the bleeding rate post-SRS after a latency
detection rate of cavernous angioma. The annual period of 2 years. The complication rate seems
hemorrhage rate ranges from a low 0.1–0.7% in higher than expected, compared to similar treat-
patients who never bled to a high 30–35% for ment of arteriovenous malformations.
Author, Total # of Age

year patients (years) Treatment Results Notes
Gao et al. 343 Not Systematic review Outcomes were compared A systematic review
(2020) available from 9 studies using to over 2000 patients comparing two
SRS. No technical treated surgically. Overall treatment modalities
details of treatment. seizure control rate was in patient with a
All patients had higher with the surgical history of seizure.
previous documented treatment. However, Selection bias likely
seizures permanent toxicity was to be present
lower in the SRS group
Nagy 210 Median: Gamma knife In the single-bleed group, SRS for critically
et al. 43 SRS. Median marginal the rebleed rate dropped located lesions in
(2019) dose: 12–13 Gy from 4.3% in the first patients with previous
(depending on 2 years to 1.1% after hemorrhage. Positive
location). All patients 2 years of SRS. For the results post-SRS with
with deep-seated multiple-bleed group, there a significant drop in
lesions who had a was a significant decrease rebleeding rate.
previous hemorrhage in the bleed rate from Treatments well
(39.5% had multiple 20.7% pre-SRS to 1.3% tolerated
bleeds). 42 patients 2 years post-SRS. The
had multiple lesions rates of temporary and
persistent adverse events
post-SRS were 8.3% and
7.2%, respectively,
although some of these
events may be related to
rebleeding episodes
Kim et al. 576 Mean: A systematic review The annual hemorrhage rate Important systematic
(2019) 40.2 and meta-analysis of pre-SRS was 23.35%, and it review and meta-
14 studies using SRS was 3.2% post-SRS with an analysis of patients
for brainstem lesions. overall incidence rate ratio with symptomatic
Only 5 patients never of 0.123. A significant brainstem cavernous
experienced a brain difference in the hemorrhage malformations
hemorrhage. The rate was seen after 2 years of
majority treated with SRS. Symptomatic adverse
the gamma knife. The events occurred in 7.3% of
median marginal dose patients with 2.2%
ranged from 11 to developing permanent
15.84 Gy events
(continued)
Jacobs 76 Mean: Brainstem cavernous Median follow-up of Patients with frequent
et al. 41.6 malformations. 48 months. Post-SRS hemorrhage pre-SRS
(2019) Gamma knife hemorrhage confirmed in are still at risk of
SRS. Mean marginal 20% of patients. The bleeding post-SRS,
dose: 15 Gy. Mean annual hemorrhage rate although at a
volume: 0.66 cm3. was 31% before and 4% decreased rate. Despite
Over 90% of patients after SRS. Rate of SRS- or a small lesion volume,
had experienced two hemorrhage-related rate of toxicity can be
or more bleedings. adverse events increases high. Repeated
18% had previous from 10% at the first year hemorrhages may have
surgery to 20% at 5 years contributed to adverse
events
Shin et al. 4 Median: Previously SRS treated All patients had incomplete Although most vessels
(2015) 27 patients who sclerosis of the vessels. were obliterated,
developed a bleeding Three patients showed hemorrhage post-SRS
posttreatment and pathological changes may be related to
underwent surgical compatible with incomplete sclerosis of
removal of the neovascularization smaller patent vessels.
cavernous Presence of
malformations neovascularization
suggests continuous
production of
angiogenic factors
Lee et al. 49 43 Brainstem cavernous At a mean follow-up of Significant
(2014) malformations. 64 months, the annual improvement in the
Gamma knife hemorrhage rate (AHR) AHR after treatment
SRS. Mean marginal ≤2 years post-SRS was 7% even after a single
dose: 13.1 Gy. Patients in group A and decreased bleeding episode.
divided into two to 2% after 2 years of Treatment well
groups: (a) had one SRS. The calculated AHR tolerated
previous single bleed prior to SRS in group B
(31 patients); (b) had was 38.36%. It decreased
two or more bleeding to 9.84% in the first 2 years
episodes (18 patients) post-SRS and to 1.5% after
2 years of SRS. Overall
toxicity rate was 8.2%
Monaco 68 Mean: Gamma knife The mean follow-up time One of the largest
et al. 41.2 SRS. The mean margin post-SRS was 5.17 years. series of brainstem
(2010) dose was 15.84 Gy. The calculated cavernous angiomas
The mean volume of pretreatment annual treated by SRS
the malformation was hemorrhage rate was
1.19 cm3 32.38%. Post-SRS annual
bleeding rate in the first
2 years was 8.22%. It
dropped to 1.37% after
2 years. 12% of patients
developed neurological
symptoms related to SRS
Liu et al. 125 Not Gamma knife The mean follow-up was Post-SRS, the authors
(2005) available SRS. Mean dose: 5.4 years. The mean lesion observed an
12.1 Gy. 77.5% had volume was 3.12 cm3. The improvement in
previous hemorrhage annual rebleeding rate pre-SRS symptoms
post-SRS in the first 2 years and a drop in the
was 10.3%. It decreased to annual rebleeding rate
3.3% after 2 years.
Symptomatic adverse
events in 2.5% of patients
(continued)
302 L. Souhami
(continued)
Tsien 20 Median: Linac-based In 127 patients, lesion was in Results showed
et al. 41 SRS. Median dose was the brainstem. Median significant decrease in
(2001) 25 Gy follow-up of 77 months. the annual
Annual hemorrhage rate hemorrhage rate
dropped from 30% pre-SRS post-SRS
to 3.2% post-SRS. SRS-
related complications seen in
20% of patients, but
permanent in only 1 patient
(5%)
Moriarity 68 Mean: Patients diagnosed by The mean follow-up was Study on the natural
et al. 34.6 MRI and followed 5.2 years. 19% of patients history of cavernous
(1999) prospectively between were familial cases. 37% had malformations
1987 and 1996 without multiple lesions. 13% had a
treatment prior hemorrhage. In 81%,
the lesion was supratentorial.
The annual overall bleeding
rate was 3.1%, all occurring
in patients without a
previous hemorrhage history
Chang 57 Mean: 47 patients treated All patients had a previous Long-term follow-up.
et al. 35.6 with helium ion and 10 hemorrhage. Mean follow-up No obvious difference
(1998) with Linac-based of 7.5 years. Post-SRS in outcome between
SRS. Mean equivalent bleeding rate was 9.4% in the two treatment
dose was 18 Gy. Mean the first 3 years and 1.6% modalities
lesion volume was after 3 years. Complications
2.25 cm3. Eight seen in 9 patients
patients had post-SRS (symptomatic edema in 7,
surgery due to necrosis in 1, and increased
bleeding seizure frequency in 1)
Karlsson 22 Not Gamma knife 16 patients had previous Because of the
et al. available SRS. Dose hemorrhage. The bleeding limited protection
(1998) prescription varied rate post-SRS was 8%. against hemorrhage
from a median of SRS-related complications and the high
18 Gy (minimum occurred in 27% of patients complication rate, the
dose) to a median of at a median time of authors did not
33 Gy (maximum 12 months. Complications recommend SRS for
dose). 15 Gy or less were more frequent in the these lesions
was considered low high-dose group
dose. Half of the
patients received low
and half the high dose
Amin- 95 Mean: Patients treated at the 77% of patients experienced Although the
Hanjani 36.5 Harvard Cyclotron prior hemorrhage. The hemorrhage rate
et al. between 1977 and calculated annual diminishes
(1998) 1993. Proton bean hemorrhage rate pre-SRS posttreatment, the
therapy delivered a was 17.4%. After a mean complication rate was
median margin dose follow-up of 5.5 years, the significant
between 15 and annual hemorrhage rate
16.5 Gy, depending decreased to 10.4%
upon the size of the post-SRS. After a latency
lesion. Median lesion period of 2 years, the annual
volume was 3.1 cm3 hemorrhage rate was 4.5%.
Radiation-induced
complications were seen in
26.5% of patients with the
majority left with permanent
deficit
3 Coronary and Peripheral 2000, the Food and Drug Administration

Arterial Stenosis approved the use of EVBT for coronary artery in-
stent restenosis. With the introduction of drug-
The limitations of balloon angioplasty and percu- eluting stents, the incidence of coronary
taneous arterial stent implantation in the treat- restenosis was reduced to 10% or less in selected
ment of arterial stenosis include a relatively high patients and the use of EVBT dramatically
rate of reocclusion (~25%) and restenosis (~30– decreased. However, even with drug-eluting
50%) due to intimal hyperplasia. This inflamma- stent, there is persistent restenosis and the risk of
tory response (fibroproliferative reaction) is thrombosis is not nil. There has been no random-
triggered by trauma of the luminal wall during ized trial comparing restenosis rates after drug-
stent placement. The potential benefit on the use eluting stent with or without EVBT. The use of
of radiotherapy was initially shown in 1992 in EVBT in the reduction of restenosis has histori-
animal models. In 1994, the first human study cal supporting evidence, and its beneficial thera-
using endovascular brachytherapy (EVBT) in peutic use should not be summarily dismissed.
patients with restenosis or reocclusion of the In-stent coronary restenosis even with drug-
superficial femoral artery was reported. Further eluting stents remains challenging, and EVBT
to that, in 1997, the first study in patients with offers a high rate of success with an excellent
coronary restenosis was published. Many studies, toxicity profile. Further well-designed, controlled
including randomized trials, involving patients trials with clinically relevant outcomes, including
with arterial stenosis treated with EVBT after quality of life and health economics, comparing
percutaneous transluminal angioplasty (PTA) or EVBT to modern endovascular approaches are
stent placement showed a benefit to EVBT. In warranted.

Peripheral stenosis
Therasse 70 Mean: Randomized trial using At 2 years, restenosis was This randomized
et al. 66 external beam more frequent in the irradiated study using
(2016) radiotherapy to prevent group: 68% vs. 44% external beam
restenosis after stenting (p = 0.003). Stent thrombosis radiotherapy did
of the superficial was also more frequent in the not show a
femoral artery. Dose: radiotherapy arm (33 vs. 13%, benefit for a
14 Gy (single session) p = 0.003). Target lesion single dose of
vs. 0 Gy (sham revascularization was similar 14 Gy over sham
radiation). 6 MV Linac between groups irradiation
and 3-dimensional
conformal technique
used. Endpoint was rate
of angiographic
restenosis 2 years
post-stenting
Andras A meta-analysis of 8 trials were found and Although,
et al. randomized trials of the selected. All studies used the overall,
(2014) use of EVBT as femoropopliteal artery. All randomized trials
adjuvant therapy to the studies compared PTA with or favor the use of
endovascular without stenting plus EVBT EVBT, this
approaches of patients vs. the same without meta-analysis
with peripheral vascular EVBT. Cumulative patency questions the
disease vs. no was higher at 254 months in inconsistency of
brachytherapy the EVBT cohorts. Significant assessment and
differences favoring EVBT reporting of
for restenosis at 6 and clinically relevant
24 months. Similar findings outcomes
for target lesion
revascularization
(continued)
304 L. Souhami
(continued)
Silverman 21 Median: Patients with renal At a median follow-up time of Retrospective
et al. 82 artery in-stent restenosis 42 months, only one patient small series.
(2014) <30 months post-initial developed restenosis. The Impressive
stenting. Treatment mean patency post-EVBT was results
consisted of PTA 44 months compared to
followed by 11 months prior to EVBT
EVBT. EVBT (p < 0.0001)
performed with Sr90/Y90
(beta emitter). The dose
delivered was 18.4 Gy
at 2 mm from the
catheter
Wolfram 44 Mean Vienna-5 trial. All patients received assigned This small,
et al. 67.7 Double-blinded treatment. The overall double-blinded,
(2005) randomized trial of recurrence rate was 35% in randomized study
post-PTA and stent the PTA-alone group vs. 33% did not show a
implantation comparing in the EVBT group (p = 0.89) benefit for EVBT
EVBT vs. sham EVBT in preventing
in the prevention of restenosis. High
femoropopliteal incidence of early
restenosis. Ir192 source and late
used and a dose of occlusions
14 Gy prescribed at
2 mm into the arterial
wall. Endpoint was
restenosis at 6-month
angiographic
assessment
Pokrajac 67 >40 Vienna-3, double- Mean follow-up of Relatively large
et al. blinded, randomized 15.7 months. Brachytherapy number of patient
(2005) trial. Ir192 high-dose-rate was well tolerated. The exclusions.
EVBT. Dose prescribed: restenosis rate was 41.7% in High-risk
18 Gy at 2 mm into the the EVBT cohort and 67.1% patients. Result
arterial wall. De novo in the placebo cohort outcomes better
(minimum of 5 cm (p < 0.05) than the previous
stenosis) or recurrent Vienna-2 trial
femoropopliteal lesions
allowed. Following
angioplasty, patients
randomized to EVBT or
no further therapy
(sham irradiation used).
EVBT was delivered
with a centering
catheter. Endpoint was
patency at 12 months
Gallino 81 (EVBT Mean: Four-arm randomized Restenosis was significantly Although
et al. alone) and 72 and trial EVBT alone vs. higher in patients not probucol reduced
(2004) 83 (EVBT 71 EVBT + probucol vs. receiving EVBT restenosis when
plus probucol vs. control compared to
probucol) after PTA of the control, it had no
femoropopliteal artery. additive effect
Ir192 EVBT prescribed when combined
dose of 14 Gy at 5 mm. with EVBT
Endpoint was restenosis
at 6 months
(continued)
Krueger 15 Randomized study Groups comparable. Small
et al. comparing EVBT vs. no Follow-up angiography, randomized
(2004) irradiation after PTA for duplex ultrasonography, and study. Similar
de novo femoropopliteal treadmill testing done at 6, 12, results at
stenosis. EVBT dose and 24 months. Degree of 24 months.
was 14 Gy stenosis significantly Target vessel
decreased in the EVBT group retreatment was
at 6 and 12 months more frequent in
the irradiated
group
Chan 1 37 Patient with severe Repeat carotid angiography at Case report of
et al. bilateral carotid 6 months showed no evidence successful EVBT
(2003) stenosis. Underwent of recurrence of restenosis. for carotid
bilateral carotid The patient was clinically restenosis
stenting. 12 months well at 10 months post-EVBT
later, patient developed
restenosis. Underwent
repeat angioplasty
followed by Ir192
brachytherapy. Dose
prescribed: 8 Gy at
4 mm from the source
Pötter Recommendations for Guidelines from
et al. prescribing, recording, the EVA GEC
(2001) and reporting in ESTRO Working
endovascular Group
brachytherapy
Stückle 1 47 Bilateral renal artery At a 6-month follow-up, First reported
et al. stenosis leading to angiography revealed no case of EVBT in
(2001) uncontrolled evidence of restenosis. Blood restenosis of
hypertension. pressure controlled renal artery.
Previously treated by Short follow-up
PTA. Angioplasty
performed again
followed by
EVBT. Treatment with
Ir192. Dose prescribed:
12 Gy
Pokrajac 57 Mean: Randomized trial At a mean follow-up of Nonblinded
et al. 71 following 12 months, no complications study.
(2000) femoropopliteal PTA were seen. Crude restenosis Brachytherapy
(no stenting) of EVBT rate at 6 months was 28% in catheter was not
vs. observation. Ir192w the PTA + EVBT arm vs. 54% centered within
source used and a dose in the PTA-alone arm the vessel lumen
of 12 Gy prescribed a (p < 0.013)
3 mm from the source.
Endpoint was
femoropopliteal patency
after 6 months
(continued)
306 L. Souhami
(continued)
Minar 57 Mean: Randomized trial of The mean follow-up time was This was the first
et al. 71 PTA alone vs. the same 12 months. Follow-up clinical randomized trial
(2000) plus EVBT for patients information available in most showing the
with femoropopliteal patients and angiographic data benefit of EVBT
restenosis. Specific in 64%. There was a in preventing the
criteria for patient entry. significant lower recurrence recurrence of
EVBT delivered by Ir192 rate in the group receiving restenosis in
source and a reference EVBT at 6 months (28.3% vs. patients
dose of 12 Gy was 53.7%, p < 0.05) undergoing
prescribed at 3 mm PTA. Treatment
from the source. was not blinded
Clinical and
angiographic follow-up
done at several periods
posttreatment
Bottcher 13 Mean: Patients with Follow-up time ranged from 3 First report on
et al. 69.3 femoropopliteal to 27 months. The stented the use of EVBT
(1994) stenosis. EVBT using a area treated remained patent to prevent stent
high-dose-rate in all patients with no restenosis. Study
brachytherapy unit with evidence of restenosis. No limited by small
an Ir192 source. Dose of complications reported number of
12 Gy prescribed at patients and
3 mm from the source limited number
of follow-up
angiography
Total #
Author, of Age
Coronary stenosis
Varghese 197 Mean: Retrospective study The primary endpoint was This study suggests
et al. 65 including only patients significantly lower in the benefit for the use of
(2018) with chest symptoms EVBT cohort in comparison to EVBT at the time of
requiring another controls (13.2% vs. 28.2%, repeat angioplasty in
percutaneous coronary p = 0.01). No difference in patients who
intervention due to death or myocardial infarction developed restenosis
restenosis after previous rates. In a propensity-matched after the implantation
implantation of a analysis, the use of EVBT of drug-eluting stents
drug-eluting stent. reduced significantly major
Comparison of outcomes cardiac events and of target
between those who lesion revascularization
received post-angioplasty
EVBT or not. EVBT
delivered with 90Sr/90Y to
a dose ranging from 18.3
to 23 Gy from the center
of the source. The
primary endpoint was the
development of major
adverse cardia event at
12 months
(continued)
Total #
Author, of Age
Negi 186 Mean: EVBT for recurrent Minimum follow-up of Lower recurrence rate
et al. 65 in-stent coronary 3 years. 95% of patients had post-
(2016) restenosis post-drug- >2 episodes of target lesion EVBT. Treatments
eluting stent. Selected revascularization prior to well tolerated
patients undergoing EVBT. Post-EVBT target
percutaneous coronary revascularization was 3.3% at
intervention received 6 months, 12% at 12 months,
EVBT with 90Sr/90Y. The 19% at 2 years, and 21% at
prescribed dose ranged 3 years. One patient had
from 23 to 25 Gy at thrombosis at 3 years
2 mm, based on vessel
diameter, from the center
of the source. EVBT
followed balloon
angioplasty
Alli et al. 125 Mean: Randomized study There were no differences in The early and
(2012) 63.5 comparing efficacy and target lesion revascularization midterm benefits
safety of sirolimus-eluting or target vessel failure (cardiac reported with the
stent vs. EVBT in patients death or myocardial drug-eluting stent over
treated for coronary infarctions) between the two EVBT are no longer
in-stent restenosis of arms seen with long-term
bare-metal stents. EVBT follow-up
delivered by either β or γ
brachytherapy. Endpoints
were cardiac death,
myocardial infarction, or
target vessel
revascularization at
9 months
Schukro 17 Mean: Randomized trial of Comparable groups (20 Worse outcome for
et al. 60.8 β-brachytherapy vs. patients in eluting stent brachytherapy cohort
(2007) paclitaxel-eluting stent cohort). Significant control of seen in terms of
implantation after restenosis in the drug-eluting restenosis
angioplasty in patients stent arm. No difference in
with diffuse in-stent clinical outcome and late
restenosis. lumen loss
β-brachytherapy with
90
Sr/90Y to a prescribed
dose of 18 Gy at 1 mm
vessel wall depth. Primary
endpoint was restenosis
and adverse clinical events
Sheppard Literature review At the time of review, a total of Review suggests that
et al. regarding intracoronary 1047 patients had entered the catheter-based
(2003) brachytherapy post- randomized trials. Radiation intracoronary
percutaneous coronary dose ranged from 14 to 30 Gy. brachytherapy is
revascularization. Animal The rate of restenosis in the useful in preventing
and human studies radiotherapy group varied from in-stenting restenosis
reviewed. Authors 8% to 33% vs. 39% to 64% of post-percutaneous
examined outcomes from patients receiving placebo coronary
7 randomized trials in revascularization
humans comparing
catheter-based
intracoronary
brachytherapy to placebo
(continued)
308 L. Souhami
(continued)
Total #
Author, of Age
Popma 244 Mean: Multicenter randomized, Target-vessel revascularization First multicenter
et al. 61.5 double-blinded, trial for was seen in 17% of patients randomized trial.
(2002) patients with a single receiving radiation vs. 26.8% Largest reported
target site of in-stent of the patients assigned to randomized study
anastomosis. Treatment placebo (p = 0.015). ≥50% showing the
delivered by a 90Sr/90Y stenosis was also more effectiveness of β
source. Dose varied frequent in the placebo group therapy in preventing
between 18.4 Gy for (p = 0.001) the recurrence of
vessel sizes >2.7 mm and in-stent restenosis
≤3.35 mm and 23 Gy for
vessel sizes >3.36 and
≤4 mm. The endpoint
was target
revascularization and a
≥50% stenosis within the
treated vessel
Leon 131 Mean: Double-blind randomized The clinical outcome of the This study is a
et al. 58 trial with 252 patients need for a repeat follow-up from
(2001) with in-stent coronary revascularization was previous reports from
restenosis. Primary significantly improved in the the same institution
endpoint was to compare group assigned to EVBT. The with a larger number
clinical outcome at incidence of thrombosis and of patients. Despite a
9 months posttreatment. late myocardial infarction was lower rate of
EVBT Ir192 dose was increased in the EVBT group restenosis in the
8 Gy to the target farthest EVBT group, more
from the source to 3 Gy thromboses were seen
to the target closest to the with an increased
source number of myocardial
infarctions. The
authors questioned the
validity of the
procedure
Waksman 65 Mean: Randomized trial for At 6 months, a significant Study confirmed the
et al. 63.2 patients with in-stent number of patients in the beneficial
(2000) coronary restenosis. 130 EVBT arm required less target improvement with
patients entered. lesion and vessel EVBT
Post-angioplasty or stent revascularization compared to post-angioplasty
implantation, patients placebo group
randomized to EVBT vs.
placebo. EVBT (Ir192)
dose: 15 Gy prescribed at
2–2.4 mm from the
source
Teirstein 26 Mean: Patients randomized to In EVBT-treated patients, Long-term follow-up
et al. 69.8 post-stenting EVBT vs. target-lesion revascularization of a randomized trial
(2000) placebo was reduced by 74% at originally published in
6 months and 68% at 3 years. 1997 confirming
Angiographic restenosis was initial results
reduced by 69% at 6 months
but only 48% at 3 years
(continued)
Total #
Author, of Age
Teirstein 26 Mean: Randomized trial Groups were comparable. At a First randomized trial
et al. 69.8 comparing post-stenting mean follow-up time of comparing EVBT vs.
(1997) EVBT vs. placebo in 12.2 months, stenting plus placebo in patients
patients with coronary EVBT significantly reduced with coronary
restenosis post-stent angiographic and clinical restenosis.
placement. Investigators indexes of restenosis Preliminary results
were blinded to the
treatment arm. EVBT
dose was 800 cGy to the
target farthest from the
source to 3000 cGy to
the target closest to the
source
Condado 21 Mean: EVBT using high-dose- At the 6-month follow-up, 20 First report of
et al. 52 rate Ir192 source. arteries remained patent. Two intraluminal
(1997) Prescribed dose was arteries developed total radiotherapy in the
25 Gy in 9 patients, occlusion. No complications coronary arteries of
20 Gy in 11 patients, and reported humans
18 Gy in 1 patient.
Intracoronary
radiotherapy was
delivered after
percutaneous
transluminal coronary
angioplasty. 22 arteries
treated. Angiographic
follow-up was performed
at 24 h, between 30 and
60 days, and at 6 months
4 Dural Arteriovenous Fistulas cannot be determined and they are considered

(Brain) idiopathic. They are usually classified in low- or
high-flow lesions. The clinical presentation
Dural arteriovenous fistulas (dAVFs) are abnor- depends on the site and the hemodynamics of
mal shunts between the arterial and the venous the lesion. Patients may present with pulsatile
systems located within the dura in which menin- tinnitus, diplopia, exophthalmos, papilledema,
geal arteries shunt blood directly into the dural seizures, and neurological deficits. Intracranial
sinus or leptomeningeal veins. They comprise hemorrhage occurs mostly in cortically based
10–15% of all intracranial vascular lesions. lesions, with an overall risk of hemorrhage of
dAVFs are more frequent in the infratentorial about 2% per year. Thus, dAVFs with cortical
compartment, whereas they constitute 35% of venous drainage are considered high risk. Three
infratentorial malformations. The most common classifications are used to categorize dAVFs’
locations include the cavernous sinus, the cribri- natural course based on the angiographic evi-
form plate, the transverse sigmoid sinus, and the dence of cortical venous drainage (Borden,
tentorium. The etiology of these malformations Cognard—most used—and Barrow). The man-
is not fully understood. In contrast to the major- agement of these lesions includes observation,
ity of intracranial malformations, dAVFs are surgical removal, endovascular embolization, or
believed to be acquired vascular lesions due to stereotactic radiosurgery (SRS). These thera-
thrombosis, inflammation, or trauma of the peutic strategies can be used alone or in combi-
dural sinus. Not infrequently, the real etiology nation. Intervention is recommended for patients
310 L. Souhami
with severe symptoms, high risk of bleeding, or resulting in a complete obliteration rate ranging
progressive neurological deficit. SRS is an from 60% to 68% and a low complication rate.
attractive therapeutic option for patients not Latency period for obliteration ranges from 1 to
amenable to surgical or endovascular approach 3 years or more.
Total #
Author, of Age
Starke 114 Mean: 55 Gamma knife SRS. Mean Follow-up duration is Multicenter
et al. margin dose: 21.8 Gy. 25% 46.7 months. dAVF international
(2020) of patients received margin obliteration was retrospective study. On
dose >25 Gy. Post-SRS confirmed in 68.4% of multivariable analysis,
follow-up angiogram done patients. Post-GKRS predictors of
in 66.6% of patients actuarial rates of unfavorable outcome
obliteration at 3, 5, and were margin dose
10 years were 41.3%, >23 Gy and dAVF in
61%, and 82%, tentorial or middle
respectively. Median fossa location. Female
time to obliteration was gender, absent venous
39 months. Annual risk ectasia, and cavernous
of hemorrhage sinus location were
post-SRS of 0.9% associated with better
outcome
Chen 41 Mean: 52 Cohort of high-grade 13 patients (62%) No predictors for
et al. dAVFs. Only 21 patients achieved an obliteration. obliteration identified
(2018) evaluable. Prior Treatments well
embolization in 13 patients tolerated
and prior surgery in 5.
Median margin SRS dose:
20 Gy
Tonetti 40 Mean: 61 Only dAVFs with cortical After a mean follow-up Overall symptomatic
et al. venous drainage included. of 2.9 years, an complication rate
(2018) dAVFs classified in obliteration rate of 62% post-SRS was 2.4%.
nonaggressive vs. was seen. Obliteration No complication
aggressive based on rate higher in documented in
neurologic symptoms or nonaggressive dAVFs. nonaggressive dAVF
bleeding. 19 patients had Overall hemorrhage rate
nonaggressive dAVFs. post-SRS was 2.4%
Gamma knife SRS. dAVFs
divided in volume <2 cc
(50% of patients) vs. >2 cc.
Margin dose was based on
volume: mean dose of
21.5 Gy for smaller dAVF
and 20 Gy for larger. 28
patients (78%) also
received embolization
Tonetti 19 Mean: 54 SRS mean marginal dose: Angiographic follow-up Pooled analysis from
et al. 20 Gy. 14 patients in 11 patients at a the literature to
(2017) underwent embolization median follow-up of delineate symptom
2.2 years. Obliteration improvement (pulsatile
rate of 82% achieved tinnitus and ocular
No complications findings) in low-risk
reported. dAVFs confirmed
Symptom improvement significant
(pulsatile tinnitus) improvement post-SRS
occurred in 92% of
patients
(continued)
Total #
Author, of Age
Chen 729 Mean: A systematic review of 19 Mean overall follow-up: A comprehensive
et al. ranged selected papers using 30 months. Post-SRS systematic review with
(2015) from 50 SRS. In 15 papers, gamma angiography done in inherent limitations of
to 69 knife used and in 3 40% of patients. Overall retrospective studies
Linac-based SRS. No complete obliteration
information in one paper. rate was 68%. It was
Previous embolization done 87% in angiographically
in 28.5% of patients and followed patients.
microsurgery in 5% Complication rate was
1.3%. 0.3% died
Zaidi 17 Mean: Multimodal treatment. Overall complete dAVFs are less
et al. 6.4 12.5% received obliteration rate was common in the
(2015) radiosurgery. Majority 87.5%. The overall pediatric population.
underwent embolization complication rate was Usually complex
19% lesions requiring
multimodal treatment.
Complications tend to
be higher in this group
Piipo 16 Not Linac-based SRS. Median Complete obliteration Small sample of
et al. available marginal dose: 18 Gy. SRS rate of 75% in SRS-only selected patients from a
(2013) as an adjuvant in 13 treated patients and 50% cohort of 251 patients
patients (81%) when combined with
embolization
Pan et al. 318 Mean: Gamma knife Mean follow-up of One of the largest
(2013) 57.8 SRS. Marginal dose: 24 months. 262 patients institutional series.
17.2 Gy. 54 patients (17%) with imaging follow-up.
had either endovascular For the cavernous sinus
embolization or surgery dAVFs, the complete
obliteration rate was 70%.
It was 59% for the
non-cavernous sinus
dAVFs. Only two patients
had post-SRS intracranial
hemorrhage. 98% had
stable or improved clinical
condition post-SRS
Gross and 8 Mean: Linac-based SRS. Mean Obliteration seen in 8/9 Good literature review
Du (2012) 56.8 dose of 17.7 Gy. 4 patients patients (89%) at a
underwent embolization. median follow-up of
Cortical venous drainage in 2.9 years
6 patients
Cifarelli 55 Mean: 50 Gamma knife SRS. Mean Angiographic MRI in 4 of 33 patients
et al. dose of 21 Gy. 11 patients assessment within (12%) showed imaging
(2010) (20%) had undergone 3 years done in 46 changes
previous craniotomy and patients. A complete
36 (55%) previous obliteration rate was
embolization seen in 30 patients
(65%)
Yang 40 Median: 28 patients had SRS up Median follow-up of SRS and embolization
et al. 60 front (before or after 45 months. Obliteration proved to be superior
(2010) embolization) and 12 had rate varied based on than SRS alone.
delayed SRS for residual or up-front SRS (83%) or Cavernous location
recurrent dAVFs. Gamma SRS alone (67%) associated with better
knife SRS. Median outcome
marginal dose: 21 Gy
(continued)
312 L. Souhami
(continued)
Total #
Author, of Age
Pan et al. 20 Mean: 53 SRS dose ranged from 16.5 Median follow-up of dAVFs involving the
(2002) to 19 Gy prescribed to the 19 months. 14 patients transverse-sigmoid
50–70% isodose surface. (74%) reported sinus
Before SRS, 9 patients had symptom improvement.
undergone surgery and/or 11 patients (58%)
embolization achieved a complete
obliteration based on
MRI assessment.
Follow-up angiogram
done in 11 patients
showed complete
obliteration in all of
them
O’Leary 17 Mean: 56 Gamma knife SRS. Dose: Adequate follow-up in One patient became
et al. 25 Gy. Dose prescribed to 14 patients. Follow-up totally deaf, probably
(2002) the 50% isodose surface ranged from 8 to from treatment. First
96 months. 6 patients report of SRS in dAVFs
had symptomatic from the United
improvement. 2-year Kingdom
angiogram done in 13
patients showed
complete obliteration in
10 (77%)
Guo et al. 18 Mean: 55 Gamma knife SRS. Mean Obliteration rate of 80% Lesions located in the
(1998) marginal dose: 28 Gy by angiography cavernous sinus only
No complications
reported
Link et al. 29 Mean: 61 Gamma knife SRS Mean follow-up: SRS followed by
(1996) followed by embolization 21 months. embolization was felt
in selected cases (17 Embolization reduced to be safe and effective
patients). Mean dose of (10 patients) or reduced
19.2 Gy prescribed to the (2 patients) retrograde
50–60% isodose surface. cortical or pial venous
Embolization was done drainage. 15 patients
within 48 post-SRS experienced
symptomatic
improvement.
Angiography in 18
patients showed
complete obliteration in
13 (72%)
Lewis 9 Mean: 61 7 patients treated with At a mean follow-up of Selected group of
et al. embolization and Linac- 24 months, 4 patients tentorial dAVFs
(1994) based SRS. Median dose (57%) achieved
was 17 Gy complete obliteration.
One transient radiation
injury
(continued)
Total #
Author, of Age
Chandler 1 74 Linac-based SRS. 30 Gy Follow-up angiogram at Slow obliteration over
Jr and prescribed to the 80% 3 years showed the years
Friedman isodose and delivered in a complete obliteration
(1993) single session
Barcia- 20 Median: Co60-based radiosurgery. Complete obliteration in No toxicity reported
Salorio 59 Dose ranged from 36 to 90% of patients
et al. 40 Gy (median 40 Gy). In 2
(1991) cases, a second dose of
40 Gy was delivered
Yamada 12 Median: External beam radiotherapy 11/12 patients (91.5%) Authors recommended
et al. 60.5 (Co60). Median dose was achieved complete this treatment as the
(1984) 4800 rad given 2–3 disappearance of dAVF first option for dAVFs!
fractions weekly by angiography. No
complications reported
Bitoh 2 72 and Both patients treated with The first patient had No complications
et al. 69 Co60 megavoltage. One marked improvement in reported. Paper lacks
(1982) patient received 3200 rads her symptoms. No technical details of
delivered in 18 days and angiographic follow-up treatment
the other received The second patient
30,124 rads delivered in achieved a complete
17 days angiographic
disappearance of the
lesion 6 months
post-radiotherapy
Houser 28 Range: Authors review radiologic Results not described Historical value
et al. 20–70 findings. 15 patients treated
(1972) by surgery and 1 by
radiotherapy. Details not
available
5 Hereditary Hemorrhagic may also present with bleeding from visceral

Telangiectasia (Osler-Weber- organs if the vascular beds of these organs are
Rendu Syndrome) involved. Iron-deficiency anemia is common.
The diagnostic criteria of HHT include epistaxis,
Hereditary hemorrhagic telangiectasia (HHT), telangiectasia (lips, oral mucosa, finger, nose),
also known as Osler-Weber-Rendu syndrome, is visceral involvement, and a family history. The
a rare (prevalence rate: 1 in 5000–10,000 indi- diagnosis is considered definitive if three criteria
viduals) inherited autosomal dominant angiodys- are present and possible or suspected if two crite-
plastic disorder that can affect the vasculature of ria are present. In some situations, the diagnosis
numerous organ systems, including the gastroin- is confirmed by the finding of a pathogenic
testinal tract, the lung, the liver, and the brain sequence variant in ENG, ACVRL1, or SMAD4.
(multisystem vascular malformations). Patients This review deals with HHT involving the nasal
frequently present with recurrent epistaxis but mucosa.
314 L. Souhami
Total #
of Age
Author, year patients (years) Treatment Results Notes
Aoishi 1 81 External beam Bleeding stopped after Case report. Good
et al. radiotherapy using radiotherapy. After an response to treatment
(2013) intensity-modulated 8-month follow-up, the on a patient who
technique. Dose of epistaxis remained failed many previous
50 Gy delivered in 25 controlled treatments. Short
daily fractions. Nose follow-up
packing done during
radiotherapy and
removed 2 weeks
posttreatment
Niyazi 1 69 External beam Endoscopic control Case report. Excellent
et al. radiotherapy with posttreatment showed control of epistaxis
(2010) intensity-modulated avascular nasal mucosa post-radiotherapy on
technique used. without any evidence of a patient who had
Tamponade of nose was bleeding. Previously failed several
performed during the hemangiomas and crusts previous intranasal
radiotherapy and had disappeared coagulations and
removed 2 weeks arterial embolization.
posttreatment. A dose of Follow-up is short
50 Gy was given in 25 and duration of
daily fractions bleeding control
unknown
Harwood 1 59 The patient received Nose bleeds controlled for Case report.
et al. external beam the duration of follow-up Intractable epistaxis
(2002) radiotherapy to a dose of (12 months). This was the on a patient with
40 Gy delivered in 20 first time in 25 years that strong family history
fractions to the entire the patient became of HHT. Multiple
nasal cavity using 3D epistaxis free. Treatment previous treatments
planning. 10 MV was well tolerated (slight with embolization and
photons used dry nose and mouth cautery failed to
reported) control bleeding.
Excellent response
from radiotherapy in
a short follow-up
Escalante 2 47 and Both patients treated Both patients presented Relatively short
et al. 63 years with cobalt therapy. A with uncontrolled epistaxis. follow-up. Patients
(1988) direct anterior field Bleeding slowly decreased had long-standing
covering the nasal fossa in intensity and was history of nasal
and choanae was used to controlled at 14 months in bleeding. They
deliver a dose of 45 Gy, one patient and at 8 months presented with grade
prescribed at the choanae in another 5 epistaxis in the
depth. Treatments were Pierquin’s
given with a daily dose classification
of 4 Gy, 5 treatments (reference #10) at the
weekly time of radiotherapy.
Both had received
many previous
treatments without
major benefit
(continued)
Total #
of Age
Turcato 8 Median Patients treated by From 1985 to 1995, 8 Assessment of
et al. age: endonasal brachytherapy patients received 13 epistaxis response
(1996) 31 years using 192iridium, as treatments. In four patients, (bleeding) based on
described by Pierquin both nostrils were treated, the score developed
(1951). Endonasal tubes and one other patient by Pierquin (1957).
kept in place with nasal received a second Except for one
packing and placement treatment. At a median patient, all others
verified by orthogonal follow-up of 54.1 months, achieved a complete
films. Dose of 30 Gy 12 patients had a major control of bleeding or
prescribed to the isodose change in the intensity of a substantial
in contact with the nasal the epistaxis. Bleeding improvement
mucosa control lasted for a median
of 41.3 months. No
complications reported
Pohar et al. 43 Median As previously described 8 patients excluded from The authors do not
(1993) age 52 in Pierquin (1957) the analysis for several recommend endonasal
Five patients treated reasons. Median follow-up brachytherapy as the
prior to 1971 (3 with of 5 years. The authors first therapeutic
192
Ir, 1 with 226Ra, and 1 report improvement of option. It should be
with both). Prior to epistaxis in 24 of 33 reserved for patients
1976, dosimetry was patients (73%) at 1 year. no longer eligible for
based on a tomogram The median time to nasal coagulation
taken through the central epistaxis recrudescence was
plane. After that, 24 months. Four septal
orthogonal films were perforations seen
used for dosimetry.
Prescription was to
isodose covering the
nasal mucosa. Median
dose of 30 Gy. Each
nostril treated separately.
7 patients received 2
implants and 9 received
3
Maylin 62 Not Endonasal 17 patients treated with Assessment of
et al. available brachytherapy. radium (226Ra) and 47 with response based on
(1976) Technique is the same iridium (192Ir). Results bleeding score
reported by Pierquin between isotopes developed by Pierquin
et al. (1969) compared. 17 patients (1957). Several
treated with 226Ra, 43 with patients lost to
192
Ir and 10 patients treated follow-up. No
with 192Ir after failing 226Ra. statistical analysis
Epistaxis improved in 58% done. This study is an
of patients at 6 months and update of previous
30% after 1 year of iridium report from the group
therapy. Post-radium, The authors only
improvement was seen in recommend endonasal
50% at 6 months and 20% brachytherapy after
at 1 year. Iridium-treated failure of other
patients had a delayed therapeutic
recurrence of epistaxis approaches
compared to patients
treated with radium (20.4
vs. 13.2 months). Toxicity
higher in the radium cohort
(continued)
316 L. Souhami
(continued)
Total #
of Age
Pierquin 14 Not Under local anesthesia, 3 With a minimum follow-up Assessment of
et al. available plastic catheters (tubes) of 3 years, epistaxis control response is based on
(1969) are placed in each nasal was assessed. Of the 14 an epistaxis grading
cavity. One catheter is patients treated between score developed by
placed inferiorly on the 1960 and 1965, 8 were new the authors. No septal
floor of the nasal cavity cases and 6 were previously perforation seen.
(inferior turbinate), one in treated by radium Only one failure
the middle turbinate, and brachytherapy. For the reported
another one superiorly in newly treated patients, an
the nasal bridge. Iridium192 improvement of 60% was
wire is then inserted in the observed in the epistaxis
catheters, dosimetry control while only 33% of
calculated, and treatment re-treated cases achieved
given. Dose of 30–35 Gy similar improvement
over 2–4 days delivered to
the chosen reference
isodose. Each nostril is
treated separately
Perin and 1 60 Endonasal brachytherapy Epistaxis was only Case report of a
Lemoyne performed with a controlled for a short time complication from
(1962) catheter (tube) The patient developed nasal endonasal
containing 2 radium septal necrosis 6 years brachytherapy. Of
sources with 10 mg of posttreatment interest, the patient
radium each and placed developed
in the nasal cavity for neurological problems
24 h. Each nostril treated later and the
separately in different possibility of cerebral
occasions. Similar involvement
treatment was again entertained
done 28 months later.
Total dose delivered
unknown
Pierquin 21 Median: In the first 8 cases, one The report is limited to 18 Update of the author’s
(1957) 49 years endonasal catheter (tube) cases (3 cases lost to previous experience
with 2 radium sources follow-up) with a minimum including new
(total length of 4.5 cm) of follow-up of 4 years in 15 patients. The author
11 mg of radium-element cases. Results considered considered the
inserted in each nasal excellent in most patients. treatment effective,
cavity for 24 h. Each Epistaxis control lasting although the epistaxis
catheter delivered a dose from 6 to 24 months. One control was only
of 4500 r at 5 mm depth. single failure reported temporary. Septal
Calculated dose to the (epistaxis uncontrolled). perforation avoided
nasal septum was 9000 r Septal perforation in 9 with lower dose.
For the remaining 13 cases. No difference in Superior region of the
cases, the technique bleeding outcome between nasal fossa felt to be
changed. A catheter with the two dose schedules. underdosed and
3 radium sources (total However, septal perforation considered a potential
length of 7 cm) of higher in the technique cause for failure
5.5 mg of Ra-element using 2 tubes and delivering
each placed in each nasal a dose of 9000 r to the
cavity for 24 h. The septum
delivered dose was 2500
r at a 5 mm depth. The
dose was reduced to the
nasal septum to 5000 r
(continued)
Total #
of Age
Rafalowicz 1 50 Patient treated with An inflammatory process Case report. Short
(1953) brachytherapy. Radium seen in both nostrils 6 days follow-up. Of interest,
sources used. Both postirradiation. Few months the lower lip was also
nostrils treated. Right posttreatment, bleeding treated by the same
and left nasal conduit controlled technique and
received each a dose of 5.52 mCi delivered
5.5 mCi delivered over over 11 h and 37 min
24 h and 27 min, over a
period of 10 days
Pierquin 10 Not Two approaches used Short follow-up at the time Two cases of septal
et al. available based on the location of of original publication. necrosis in the first 7
(1951) the lesion. Good control of epistaxis treated patients.
Brachytherapy (one for endonasal lesions. No Brachytherapy
catheter with 2 radium recurrence at 1 year. technique and dose
sources of 11 mg of Cutaneous lesions then modified to one
radium element inserted decreased in size and color catheter (tube) with 3
in each nasal cavity). intensity endonasal sources of
Each tube delivered 5 mg of radium
2 mCi per 24 h for a element, each tube
total dose of 8 mCi for delivering 1 mCi par
the endonasal lesions 24 h for a total dose
and superficial to each nasal cavity of
radiotherapy (120 kV), 6 mCi. No further
no filter, at an SSD of complication seen
25 cm. Dose of 1500 r in with the new schedule
3 fractions delivered at
3-weekly interval for the
facial cutaneous lesions
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Other
Dominique Mathieu and Bill Loo
Contents 1 Amyloidosis
1 Amyloidosis 321
Amyloidosis is a group of disorders with com-
2 Benign Prostate Hypertrophy 322
mon histopathologic findings in which there is
3 Fibrosclerosis 323 extracellular tissue deposition of fibrils com-
4 Hypersalivation in Amyotrophic Lateral posed of a variety of proteins. Clinical manifesta-
Sclerosis 324 tions depend upon the type of precursor protein,
5 Hypersplenism 325 the amount of amyloid deposition, and the tissue
affected such as ocular structures, larynx, and tra-
6 Peptic Ulcer 327
cheobronchial tree. Treatment may include tar-
7 Ventricular Tachycardia 329 geted therapies, chemotherapy, surgery, and
8 Macular Degeneration 330 organ transplant.
9 Lymphoepithelial Parotid Cysts 332
10 Pancreatic Fistula and Ascites 333
11 Peyronie’s Disease 333
12 Xanthoma, Xanthogranuloma 336
References 336
D. Mathieu (*)
Department of Radiation Oncology, CISSS de
Chaudière-Appalaches, Lévis, QC, Canada
e-mail: dominique.mathieu.med@ssss.gouv.qc.ca
B. Loo
Department of Radiation Oncology, Stanford Cancer
Institute, Stanford, CA, USA
e-mail: BWLoo@Stanford.edu

322 D. Mathieu and B. Loo
Total #
Copperman 4 20–30 Gy over 10–20 Amyloid deposition did not Two patients had amyloid
et al. (2019) fractions for localized progress in any patient at progression at 2 years
periocular light-chain 1 year postradiation
amyloidosis
Pacheco 1 24 Gy in 12 fractions to Clinical improvement was
et al. (2015) tracheobronchial tree observed. The patient was
clinically and functionally
stable 1 year after treatment
Truong et al. 10 Median dose of 20 Gy in At a median follow-up of 40% of patients had acute
(2012) 10 fractions to larynx (3 6.7 years, 80% of patients grade 1–2 esophagitis. No
patients) or had local control late toxicity was observed
tracheobronchial tree (7
patients)
Khaira et al. 2 34 and 30 Gy fractionated Improvement in orbital signs
(2008) external beam following surgical debulking
radiotherapy to orbit and radiotherapy, with no
recurrence years after
treatment
Neben- 7 20 Gy in 10 fractions to All patients had a favorable One patient had grade 2
Wittich et al. tracheobronchial tree response ranging from esophagitis and one patient
(2007) symptom relief to a decrease had grade 2 pneumonitis
in the frequency of that resolved after 10 days
pulmonary infections and of treatment with antibiotics
objective improvement in and corticosteroids
pulmonary function
Cruz et al. 1 30 Gy in 15 fractions to At 14 months, the patient
(2004) larynx remained without
symptomatic or image
progression of disease
Kalra et al. 1 20 Gy in 10 fractions to Marked and prolonged
(2001) tracheobronchial tree improvement in symptoms,
effort tolerance,
bronchoscopic appearance,
and forced expiratory volume
in 1 s
Kurrus et al. 1 20 Gy in 10 fractions to Marked regression of
(1998) tracheobronchial tree endobronchial disease
10 months after treatment
Pecora et al. 1 1800 rad in 6 fractions Slight to moderate resolution. Justification for treatment
(1982) over 12 days followed Patient later required excision based on the experience of
5 weeks later by 2100 rad radiation for amyloidosis of
in 7 fractions in 14 days to larynx
eyelid and conjunctiva
2 Benign Prostate condition may be treated with drug therapy

Hypertrophy such as alpha-blockers and 5-alpha-reductase
inhibitors as well as various surgical tech-
Benign prostatic hyperplasia is an enlargement niques including transurethral resection of the
of the prostate caused by an overgrowth of prostate. Few radiation therapy groups have
cells in the transition zone of the prostate that evaluated modest irradiation and published
can lead to obstructive urinary symptoms. This their results.
Other 323
Total # of
Costleigh et al. 7 2000–2400 cGy total dose with 6 MV 4.6-year mean follow-up, 38%
(1995) photons reduction in size. 86% resolved
benign prostate hypertrophy
syndrome
Koukourakis 5 Two transurethral applications Obstruction did not recur within
et al. (1994) (3 weeks apart) of Cs137, which 12–18 months of follow-up
delivered a total of 16 Gy, at 0.5 cm
from the urethral walls (dose rate
5–7 Gy/h)
Bumpus 17 Review of three case series of patient Reduction in prostate size was
(1924) with benign hypertrophy treated by often observed, but there were no
radium clear benefits in relieving
obstructive symptoms
Young (1917) 1 On an 8-month period, the patient had The prostate decreased greatly
two massive doses of radium but complete retention of urine
(1709 mg each) and five intraurethral persisted
treatment (103 mg each)
3 Fibrosclerosis et al. 2004; Oguz et al. 2002). The histopatho-

logic findings are similar. The etiology is
Multifocal fibrosclerosis has also been termed unknown. Steroids are often tried and may be
sclerosing cervicitis, sclerosing retroperitonitis, partially useful. Radiation has been used success-
sclerosing mediastinitis, sclerosing cholangitis, fully in some patients to cause regression in
fibrosing or sclerosing orbital pseudotumor, symptoms. Cases are anecdotal and response
Riedel’s thyroiditis, and hypertrophic intracranial rates variable.
granulomatous pachymeningitis (Cankurtaran
Total # of
Morris 1 Choroidal mass was treated with external After radiotherapy, there was a
et al. beam radiotherapy when high-dose disappearance of the choroidal mass
(2000) corticosteroid and low-dose methotrexate
therapy failed
Olmos 1 Orbital lesion extending into sella, No apparent response to radiotherapy.
et al. parasellar area, cavernous sinus, clivus, 3 weeks after treatment, patient
(1993) dens, second cervical vertebrae developed cranial nerve dysfunction,
Biopsy, steroids, radiation—14 Gy in which responded to steroids
7 days
Weissler 1 Orbital lesion extending into ethmoid Improved during radiotherapy and
et al. sinus responded for 1 month, then developed
(1989) Biopsy, steroids, radiation—24 Gy to recurrent symptoms and signs,
orbit, and 20 Gy to ethmoids, over requiring exenteration
2 weeks
Orbital exenteration
Nelson 1 Retroperitoneum No improvement at 9-month follow-up.
et al. Biopsy, 1688 rad cobalt therapy Patient required surgical removal
(1968)
4 Hypersalivation of frothing can be achieved rapidly with 20 Gy in

in Amyotrophic Lateral five fractions to a port which encompasses the
Sclerosis parotid, submaxillary, and submandibular salivary
glands. Other fractionation schemes may be used
Hypersalivation in amyotrophic lateral sclerosis to dry the mouth, but these involve more clinic vis-
(ALS) is a secondary phenomenon associated with its for these preterminal patients. Dental care,
progressive difficulty in swallowing. The patient’s which ordinarily would be a consideration, usually
long-term prognosis is dismal, and palliative relief is not of concern due to the shortened survival.
Total # of
Assouline 50 10 Gy in 2 fractions (n = 30) All patients had There was no grade
et al. (2014) or 20 Gy in 4 fractions (n = 20) improvement: 46 (92%) 3–4 toxicity, and most
with 6 MV photons and 2 with a complete response side effects (34%)
opposed beam fields including and 4 (8%) with a partial occurred during RT
both submandibular glands and response
two-thirds of both parotid
glands
Bourry et al. 21 The mean dose was 19.1 Gy A positive response was
(2013) delivered in five fractions on observed in 65% of patients
17 days. 13 patients were during a mean of 7 months
treated with 5.5–6 MV
photons, and 8 were treated
with 6–15 MeV electrons
Guy et al. 16 20 Gy in 5 fractions or 18 Gy 80% of patients felt
(2011) in 4 fractions improved at 1 month and
43% at 6 months after
external radiation
Kasarskis 10 Electron beam radiation was All patients reported a In 5 of 10 patients,
et al. (2011) targeted to a single parotid reduction in the intensity anticholinergics were
gland with a total dose of and amount of drooling discontinued
15 Gy in 3 fractions
Neppelberg 14 Single fraction of 7.5 Gy Salivary secretion (mL/min)
et al. (2007) was significantly reduced
after radiation treatment,
with a mean reduction of
60% at 1 week and 51% at
2 weeks
Andersen 16 Single dose of 7.0–7.5 Gy to 16/18 (89%) patients
et al. (2001) the parotid glands and the reported satisfactory to
posterior parts of the good reduction in drooling
submandibular glands lasting up to 4–6 months
Harriman 9 8 Gy in one fraction or 8 Gy of radiation was
et al. (2001) 12.5 Gy in two fractions effective in controlling
drooling, and increasing the
dose did not improve initial
control
Other 325
5 Hypersplenism tial etiologic factors in hypersplenism. Irradiation to

reduce splenomegaly and pain must be carried out
Enlargement of the spleen may be painful and asso- cautiously, especially if the spleen is the source of
ciated with hemolytic anemia, thrombocytopenia, extramedullary hematopoiesis. Very small incre-
granulocytopenia, and, in some instances, extra- mental fractional doses in association with daily
medullary hematopoiesis. Lymphoma, leukemia, pretreatment blood counts are needed to guide ther-
sickle cell anemia, and myelosclerosis are all poten- apy. Significant palliative benefit may be achieved.
Total # of
Pistevou- 20 10 patients received two The dimensions of the spleen
Gombaki courses of 360 cGy in 6 decreased significantly. Pain-related
et al. (2015) fractions, 3 months apart Visual Analogue Score regressed
8 patients received after completion of irradiation.
980 cGy in 14 fractions During 12-month follow-up, all
One patient received patients maintained the benefit of
580 cGy in 5 fractions radiotherapy
One patient received
600 cGy in 6 fractions
Ishibashi et al. 8 Total dose ranging from Symptoms diminished or
(2015) 175 to 3000 cGy disappeared in 5/6 (83%)
symptomatic patients. A reduction in
the size of the spleen was confirmed
in 5/6 (83%) patients with
splenomegaly
Lavrenkov 32 Daily fractions of 0.5 Gy Splenic size was reduced in 79%,
et al. (2012) given 5 days per week to anemia improved in 75%, and
a total dose of 6–10 Gy thrombocytopenia improved in 64%
Kriz et al. 122 The fraction size ranged Significant pain relief was achieved 36 patients died
(2011) from 10 to 200 cGy and for 75% of the radiotherapy courses within 2 months
the total dose from 30 to given for splenic pain due to the terminal
1600 cGy nature of their
disease
Soldić et al. 11 The median dose For the courses initiated for
(2011) received was 7 Gy, and symptom control, 71% resulted in
the median dose per effective palliation. For the courses
fraction was 1 Gy initiated to treat hematologic sequels
of hypersplenism, 50% produced
desirable effects
Nazmy et al. 18 The total dose ranged All patients showed subjective
(2008) from 125 to 1200 cGy improvement regarding pain and
swelling
McFarland 17 Treatment courses 22/25 (88%) treatment courses for Patients suffered
et al. (2003) generally consisted of splenomegaly resulted in decreased few significant
two fractions of 50 cGy pain and symptoms complications
in the first week, two
fractions of 75 cGy the
second week, and two
fractions of 100 cGy the
third week
(continued)
(continued)
Total # of
Schratter- 49 Mean treatment dose 55/85 (65%) courses (group A:
Sehn et al. was 20.75 Gy 47/72, group B: 8/13) with a >10%
(2003) Group A: 72 courses of reduction of spleen volume
short-time treatment of 62/85 (79%) courses (group A:
2 Gy per fraction 57/72, group B: 5/13) with clinical
Group B: 13 courses of improvement
low-dose prolonged
treatment of ≤1 Gy per
fraction
Bouabdallah 15 The median dose of The overall response rate was 59%
et al. (2000) radiotherapy per with a median duration of 10 months
treatment was 9.8 Gy in
daily fractions of
0.4–1 Gy
Elliott et al. 23 The median dose of 46/49 (94%) courses resulted in an
(1998) radiation per course was objective decrease in spleen size.
277.5 cGy administered Reduction in spleen size was
in a median of 7.5 associated with symptomatic relief
fractions in all patients. The median duration
of response was 6 months
Paulino and 25 The dose ranged from 60 Splenomegaly and splenic pain
Reddy (1996) to 1000 cGy (median, decreased in 60% and 91% of
450 cGy) in 2–16 patients, respectively
fractions
Guiney et al. 22 The total dose given Of 31 courses given for
(1989) ranged from 125 to splenomegaly, there were 19
2400 cGy, with a median responders (61%)
dose of 550 cGy, given
over a period of
2–30 days
Roncadin 38 100 cGy was 78% of patients achieved
et al. (1987) administered weekly for hematologic response, defined as
a total dose of 10 Gy, normalization of the differential
given over 10 weeks leukocyte count, of the total blood
cell count, and of bone marrow
infiltration
Wagner Jr 17 The fraction size ranged 14/19 (71%) courses given for
et al. (1986) from 15 to 100 rad and splenic pain yielded significant
the total dose per subjective relief while 17 of 26
treatment course from 15 courses given for splenomegaly
to 650 rad, with the obtained at least 50% regression of
exception of one patient splenic size
who received 1650 rad
Aabo and 23 The median total dose In 23/30 (77%) courses given in
Walbom- was 10 Gy. Daily patients with chronic lymphocytic
Jorgensen fraction size ranged from leukemia, a response was observed.
(1985) 0.5 to 1 Gy Response was defined as reduction
in palpable spleen size accompanied
by relief of symptoms (pain,
abdominal discomfort, and
sweating) or improvement in
hypersequestration or hemolytic
anemia
(continued)
Other 327
(continued)
Total # of
Byhardt et al. 14 The most typical Most patients had a significant relief
(1975) regimen was 300– of painful splenomegaly, along with
450 rad in two to three improvement of hemogram and bone
fractions of 150 rad marrow parameters
given over 3–8 days
Greenberger 14 Median dose was All 21 treatments produced
et al. (1977) 600 rad in 9 fractions palliation of pain and 20 (95%)
resulted in reduction of spleen size
Byhardt et al. 14 Splenic midplane dose 14/18 (78%) courses resulted in
(1975) was 200–1750 rad in relief of splenic pain
3–14 days with Co60.
Field size shaped to
cover the palpable spleen
and reduced as the
spleen regressed
Cook and 117 200 rad at tri-weekly At 1 year, 86/91 (95%) of patients had
Romano intervals excellent response with relief of
(1962) symptoms, blood picture returned to
near normal, tumor fractions decreased
markedly, and patient was able to
return to a relatively normal life
6 Peptic Ulcer ications, there is no contemporary indication

for radiation use in this condition. The follow-
The discovery that H. pylori bacteria induce ing table therefore includes data of historical
many ulcers has led to antibiotic treatment interest on primary outcomes as well as com-
together with modern medication inhibiting plications such as radiation-induced nephritis,
gastric acidity such as proton pump inhibitors. coronary artery disease, and secondary
With the widespread availability of these med- cancers.
Total # of
Carr et al. 1859 1859 irradiated patients Greater than expected coronary
(2005) with volume-weighted heart disease mortality was
cardiac doses ranging from observed among the irradiated
1.6 to 3.9 Gy patients. Risk increased with the
1860 controls treated by cardiac dose
other means
Carr et al. 3719 Mean stomach dose was There was a strong evidence of
(2002) 14.8 Gy exposure-related excess
mortality from cancer of the
stomach (RR 2.6), pancreas (RR
2.7), and lung (RR 1.5)
Griem et al. 1831 Mean stomach dose of Radiotherapy was linked to
(1994) 14.8 Gy significantly high relative risks
1778 controls treated by for all cancers combined
other means (RR = 1.53), for cancers of the
stomach (RR = 2.77), pancreas
(RR = 1.87), and lung
(RR = 1.70), and for leukemia
(RR = 3.28)
(continued)
(continued)
Total # of
Lieber et al. 2049 1600–1700 cGy Three sarcomas occurred in the
(1985) 743 controls treated by irradiated group and none in the
other means control group
Griem et al. 2049 1600–1700 cGy Relative risk of 3.7 of gastric
(1984) cancer
Cocco and 463 1500–2000 cGy with 90% control at 14 years of
Mendeloff 250 kV to upper 2/3 follow-up
(1979) stomach
Findlay et al. 24 Initial dose of 650–900 rad; 16/24 complete symptomatic 83% of patients were
(1974) doses later standardized to relief 60 years or older
1500 rad in 10 fractions 5/24 failures (3 of these had Gastric ulcer (3)
over 12 days further radiotherapy and Duodenal ulcer (4)
ultimately received fully Jejunal ulcer (3)
symptomatic relief) Esophageal ulcer (2)
Esophagitis (15)
Second-part duodenal
ulcer (1)
Anselm and 36 2000 rad in 10 fractions 25/36 good results with no 29/36 were over
Schuman with Co60. One anterior and recurrence at 2-year follow up 60 years of age
(1972) one posterior portal Gastric ulcer (14)
covering the upper portion Duodenal ulcer (11)
of the stomach Stomal ulcer (6)
Esophagitis (5)
Levin (1972) 47 1900–2000 rad in 10–14 Duodenal ulcer: 16.2% All patients were
fractions with 250 kV recurrence 60 years of age or
Gastric ulcer: 4/7 no recurrence older
at 2–8-year follow-up Duodenal ulcer (37)
Gastric and duodenal ulcer: 3/3 Gastric ulcer (7)
symptom free for 3–16 years Both duodenal and
following therapy gastric ulcer (3)
Cocco and 33 2000 rad in 8–10 fractions 28/33 asymptomatic at 3-year Ages ranged from 57
Mendeloff with Co60 follow-up. 94% showed to 85 years
(1970) One anterior and one achlorhydria or greater than All were cases of
posterior held centered over 50% reduction of acid response duodenal ulcers
the upper 2/3 of the (after 6 months)
stomach
Clayman 1485 1600–1700 rad (depth 640/1485 (43%) achlorhydria or Duodenal ulcer (1251)
et al. (1968) dose) in 10–12 days greater than 50% reduction in Gastric ulcer (154)
acid for 1 year or more
Cooper et al. 20 1600 rad in 10 fractions 10/16 good-excellent All were cases of
(1968) symptomatic results (long peptic esophagitis. All
term), 5/12 achlorhydria or patients were
greater than 50% reduction in continued on a
stimulated (Histalog) acid standard medical
output program after
irradiation
Brown et al. 121 2000 rad in 6–8 fractions 87/121 good results—no Supplemental medical
(1962) evidence of recurrent ulcer treatment was also
90% achlorhydria or greater used
than 50% reduction in basal Duodenal ulcer (80)
gastric secretion in the first Gastric ulcer (23)
6 months. 55% achlorhydria or Marginal ulcer (18)
greater than 50% reduction in
stimulated (Histalog) acid
secretion in first 6 months
Other 329
(continued)
Total # of
Klein and 50 1700–2000 rad in 10–14 27/50 (54%) excellent results All were cases of
Berman fractions 11/50 (22%) good results duodenal ulcers
(1961) No medical therapy of
any type was given
after irradiation
Eichorn et al. 4 2000 rad through an All patients showed a reduction Esophageal varices
(1961) anterior field to the lower in gastric acidity with bleeding (2)
two-thirds of the stomach Hiatal hernia (1)
Postoperative
esophagitis (1)
Teplitz et al. 6 200–1000 rad at the surface 3/6 abolition or substantial The single-dose
(1961) of the mucosa decrease in basal acid secretion method used is not
Beta irradiation with satisfactory
Ru-Rhl05
Kiefer and 23 1800 rad in 10 fractions 10/23 clinically satisfactory All were cases of
Smedal results after 1–3 courses of stoma ulcer occurring
(1959) therapy after subtotal
11/12 free acid level was gastrectomy
reduced (achlorhydria in 5) at
2–6 months after therapy
Brown and 52 Antroduodenectomy and 46/52 very good results. All were cases of
Wood (1956), irradiation to 2000 rad in Remaining 6 developed duodenal ulcer
Brown et al. 10 fractions recurrent ulcer
(1952) 48 Antroduodenectomy only 37/48 very good results
5/48 moderately good result
15 2000 rad in 3 weeks 4/10 free from symptoms
2/10 minor symptoms
McGeorge 32 Radium needles. 10/32 good symptomatic results All were cases of
(1950) 2000–3000 mg h 6/32 significant symptomatic duodenal ulcer
improvement Impossible to estimate
14/18 maximum free acidity the dosage in rads to
and free acid production the gastric mucosa
(histamine) below initial level
Holman and 15 500–700 rad All cases showed a reduction in All were cases of
Lewis (1941) level of free HCl, but this duodenal ulcer
reduction was variable in
amount and duration
7 Ventricular Tachycardia verter defibrillator (ICD), surgery, catheter abla-

tion, or even organ transplant. There is an
Ventricular tachycardia (VT) is a heart rhythm emergent literature for the treatment of a high-
disorder secondary to the generation of reentry risk patient with refractory ventricular tachycar-
circuitry within the myocardium that can lead to dia with stereotactic body radiation therapy.
dyspnea, chest pain, syncope, and death. It is Information for multiple modalities including
often linked to underlying cardiac pathologies CT, cardiac MRI, SPECT, and electrographic
such as ischemic coronary disease or cardiomy- imaging is combined to accurately target the
opathy. Standard treatment consists of the use of arrhythmogenic region with a single fraction of
anti-arrhythmic medication, implantable cardio- high-dose radiotherapy.
Total #
of
Gianni 5 Single fraction of During a mean follow-up of 12 months,
et al. 25 Gy by robotic all patients experienced clinically
(2020) radiosurgery significant mid- to late-term ventricular
arrhythmia recurrence
Lloyd 10 Single fraction of The total reduction in seconds of
et al. 25 Gy detected VT was 69% (pretreatment
(2020) 1065 s/month vs. posttreatment 332 s/
month). Reduction in total ICD shocks
after SBRT was 68%
Mayinger 1 Single fraction of Patient remained without any episodes
et al. 25 Gy with of sustained ventricular tachyarrhythmia
(2020) magnetic resonance requiring ICD interventions until the last
imaging-guidance follow-up at 3 months
Cvek et al. 18 Single fraction of No patient exhibited acute elevation of To further investigate
(2019) 25 Gy troponin, pericardial effusion, or a long-term safety and
decrease in left ventricular ejection efficacy of SBRT for VT,
fraction from baseline. Two patients a prospective
gradually developed significant multicentric study was
progression of mitral regurgitation after initiated
radiotherapy. One of the patients was
treated medically (grade 3 toxicity), but
the other had to undergo mitral valve
replacement (grade 4 toxicity)
Neuwirth 10 Single fraction of With a median follow-up of 28 months,
et al. 25 Gy by robotic VT burden was reduced by 87.5%
(2019) radiosurgery compared with baseline
Robinson 19 Single fraction of The median number of VT episodes was
et al. 25 Gy reduced from 119 (range, 4–292) to 3
(2019) (range, 0–31; P < 0.001)
Jumeau 1 Single fraction of While the patient could not be extubated
et al. 25 Gy by robotic because of incessant VT the week before
(2018) radiosurgery SBRT, no sustained VT was observed
after the SBRT and the patient was
extubated 3 days following the
procedure
Cuculich 5 Single fraction of After the 6-week blanking period, there The mean left ventricular
et al. 25 Gy were 4 episodes of ventricular ejection fraction did not
(2017) tachycardia over the next 46 patient- decrease with treatment
months, for a reduction from baseline of
99.9%
Loo Jr 1 Single fraction of Decrease in total VT episodes from an
et al. 25 Gy by robotic average of 562 episodes per month in
(2015) radiosurgery the 2 months pre-SBRT to an average of
52 episodes per month in months 2–9
post-SBRT
8 Macular Degeneration blindness in people over the age of 50. Treatment

may involve multiple modalities such as laser
The natural history of macular degeneration due photocoagulation and anti-VEGF injectables.
to subfoveal choroidal neovascularization of Radiation has been used in an attempt to prevent
membranes is one of progressive visual loss lead- the proliferation of endothelial cells necessary
ing to blindness. This problem of age-related for neovascularization and to induce obliteration
macular degeneration is the leading cause of of aberrant vessels. The few published reports to
Other 331
date have been encouraging, but they have used defined. Larger prospectively randomized trials
historical controls and have represented highly are needed to clarify the role of radiation in this
selected cases. The best dose and fractionation age-related chronic process.
scheme, as well as technique, remain to be
Total # of
Evans et al. 2430 Meta-analysis including There may be little or The evidence is uncertain
(2020) 18 studies with dose no difference in loss of regarding the use of radiotherapy
ranging from 7.5 to 3 lines of vision at for neovascular age-related
24 Gy. Three studies 12 months in eyes macular degeneration. Most
used brachytherapy treated with studies took place before the
(plaque and epimacular) radiotherapy compared routine use of anti-VEGF, and
and the rest external with no radiotherapy before the development of
beam radiotherapy modern radiotherapy techniques
such as stereotactic radiotherapy
Brand and 132 Stereotactic The real-world visual Stereotactic radiotherapy was
Arnoldussen radiotherapy to a total acuity outcomes for the delivered in the induction phase
(2018) dose of 16 Gy (5.33 Gy radiotherapy group of intravitreal injections of
per beam for 3 beams showed a mean gain of ranibizumab
and 8 Gy per beam for 2 +3.0 letters at
beams) 12 months
Jackson et al. 232 Patients randomized Both the 16 Gy and
(2013) 2:1:2:1 to 16 Gy plus 24 Gy SRT arms
pro re nata (PRN) received significantly
ranibizumab, sham fewer ranibizumab
16 Gy plus PRN treatments compared
ranibizumab, 24 Gy with the sham arms
plus PRN ranibizumab,
or sham 24 Gy plus
PRN ranibizumab
Marcus et al. 88 Patients randomized to At 6 months, 9 radiated Radiotherapy benefit in
(2004) radiotherapy (20 Gy eyes (26%) and 17 eyes preserving visual acuity was lost
delivered in 5 daily not radiated (49%) lost at 12 months
fractions of 4 Gy each; ≥3 lines of visual
6 MV [N = 41]) or no acuity (P = 0.04)
radiotherapy (sham
radiotherapy [N = 22] or
observation [N = 25])
Hart et al. 203 Patients randomized to At all time points,
(2002) radiotherapy (12 Gy in mean visual acuity was
6 fractions) or better in the
observation radiotherapy-treated
group than in the
control group, but the
differences did not
reach statistical
significance
Valmaggia 161 1 Gy (4 × 0.25 Gy) in The number of lines
et al. (2002) the control group and lost in the best
8 Gy (4 × 2 Gy) or corrected visual acuity
16 Gy (4 × 4 Gy) in the was less in the 8 Gy
treatment groups and 16 Gy treatment
groups than in the
control group during
the complete follow-up
examination
(continued)
(continued)
Total # of
Finger et al. 23 Palladium 103 6 months after No radiation retinopathy, optic
(1999) ophthalmic plaque radiation therapy, 3 neuropathy, or cataract could be
brachytherapy was (16%) of 19 eyes had attributed to radiotherapy within
delivered to a retinal lost 3 or more lines of this follow-up period
apex dose of 1250 to best corrected visual
2362 cGy acuity
Freire et al. 41 Most patients were At 2–3 months after
(1996) treated with a total dose treatment, 27 patients
of 14.4 Gy in eight (66%) had no change
fractions of 1.8 Gy/ in their vision
fraction over 10–13
elapsed days
Bergink et al. 40 4 groups 1. 4/10 stabilized None had regression the
(1994) patients 1. 8 Gy/1 fraction 2. 7/10 stabilized subfoveal choroidal
10 in 2. 12 Gy/2 fractions of 3. 6/10 stabilized neovascularization membranes
each 6 Gy 4. 8/10 stabilized Authors conclude that 12 or more
study 3. 18 Gy/3 fractions of will halt progression
6 Gy
4. 24 Gy/4 fractions of
6 Gy
Technique: lens-sparing
16 MV photons
Volume: 1 cm over
macula
Chakravarthy 19 10–15 Gy of 6 MV No difference in vision Vision in non-treated controls
et al. (1993) photons to the 90% between 10 and 15 Gy. deteriorated
isodose line Visual acuity
Six control patients. maintained or
Fraction size varied improved in 78% and
from 2 to 3 Gy/fx 63% at 6–12 months
9 Lymphoepithelial Parotid gland. Treatment options include repeated aspira-

Cysts tion and drainage, sclerotherapy, surgery, and
radiation therapy. Radiation has been reported to
Human immunodeficiency virus (HIV) may lead lead to significant response in a limited
to benign lymphoepithelial cysts in the parotid experience.
Total # of
Mourad 30 pts Group A: 2 Gy × 12 Complete response (CR) and partial
et al. fractions response were 80% and 13%,
(2013a, b) Group B: 1.5 Gy × 16 respectively. In group A, 100% had
fractions CR. Treatment failure was 7% and all
were in group B
Mourad 37 Group A consisted of 15 The complete response (CR) and partial
et al. patients patients (who received a response (PR) rates were 35% and 8%,
(2013a, b) total dose of ≤18 Gy, with respectively. All but 1 of 15 patients in
a median dose 10 Gy) group A had local failure (LF) with the
Group B consisted of 22 re-emergence of parotid hypertrophy.
patients who received a Among the patients in group B, 55%,
total dose of 24 Gy 13%, and 32% experienced CR, PR, and
LF, respectively
Other 333
(continued)
Total # of
Beitler 12 8–10 Gy of external All patients (100%) had at least a 50%
et al. patients radiation using 2 Gy daily decrease in the size of their parotid
(1995) fractions masses. 42% had a complete response
and 58% a partial response
Goldstein 8 8–10 Gy in 1 week 5 complete response and 3 partial Satisfactory
et al. patients response cosmesis
(1992) Mild
xerostomia
Taste loss
resolved within
1 month
10 Pancreatic Fistula ascites, reports are available of response to irra-

and Ascites diation. Documentation of conservative manage-
ment failure by a gastroenterologist is advisable
In circumstances where conservative manage- prior to consideration of radiation therapy as well
ment has failed in both pancreatic fistula and as careful informed consent.
Total # of
Kishore and Chan 1 500 rad Ascites cleared
(1991)
Hishikawa et al. 1 20 Gy 2 months later, decrease in fluid. 5 months
(1986) total closure
Ali (1979) 1 500 rad 4-day response fistula closed
11 Peyronie’s Disease genase, verapamil, interferon) and traction ther-

apy of surgery. Relief of pain of modest duration
Peyronie’s disease is a noncancerous idiopathic may be accelerated by fractionated external radi-
penile disease associated with penile deformity, ation. Issues of consideration include gonadal
pain, sexual dysfunction, and single or multiple dose, gonadal protection, realistic expectation of
indurated plaques. Evaluation of the natural results, possible remission independent of the
course of the disorder is made difficult by the treatment, and radiation-induced cancer. Patients
possibility of spontaneous resolution in contrast should be informed of these issues, and the
to cases of severe progression. Treatment of the patient/physician understanding should be
disease may be achieved with medication (colla- documented.
Total #
of
Pietsch 83 8 fractions of 4 Gy over a After a mean follow-up of Side effects included
et al. period of 6 months 52 months, 78% of the treated transient erythema
(2018) patients reported that disease in 39% of patients
progression had stopped and 47% of and 10% reported
patients had symptomatic transient or chronic
improvement dryness
(continued)
(continued)
Total #
of
Niewald 154 Most patients received a Mean duration of follow-up was
et al. total dose of 30 Gy in 15 5 years. There was an improvement
(2006) daily fractions of deviation in 47%, reduction of
number of foci in 32%, reduction of
size of foci in 49%, and less
induration in 52%. Approximately
50% reported pain relief after
radiotherapy
Incrocci 179 The RT schedule consisted 69% reported that after radiation
et al. of 13.5 Gy (9 × 1.5 Gy, 3 penile pain was diminished and 29%
(2000) fractions per week) using that penile curvature was decreased.
orthovoltage X-rays in 123 13% reported improved erections
patients or 12 Gy (6 × 2 Gy,
daily fractions) using
electrons in 56 patients
Rodrigues 38 9 Gy total on 5 alternate 9 Gy 47–65% improved
et al. days with 200–250 kV 18 Gy 20% more improved
(1995) photons
16 patients with 2 courses,
total of 18 Gy
Viljoen and 98 10 fractions of 250 cGy 84% had improved pain control and
Goedhals with 250 kV photons 38% had angulation after radiation
(1993)
Weisser 54 Total dose of 20 Gy with 69% improved
et al. 3–5 MeV electron
(1987)
Carson III 40 900 rad in average 30 plaque (4 improved)
and 32 curvature (2 improved)
Coughlin 14 pain (4 improved)
(1985) 2 erectile impotence (no
improvement)
Alth et al. 636 Radium mold, gonadal (Relief)
(1985) shield Induration 70–85%
6.6–8.2 Gy Deviation 33–53%
Pain 83–90%
Mira et al. 56 1000–1400 rad CR PR
(1980) Induration 6% 38%
Curvature 5% 33%
Pain 51% 28%
Furlow 41 250–600 rad single dose 1 treatment: Improvement of
et al. (130 kV, HVL 0.3 mm 11/22 (50%) improvement of painful intercourse
(1975) Cu-250 kV, HVL 1.5 mm curvature or erections in
Cu) 12/22 (55%) improvement of plaque average of 9 months
Field size: entire shaft of 2 treatments:
penis through a single 7/18 (39%) improvement of
dorsal port curvature
8/19 (44%) improvement of plaque
Bystrom 12 1200 rad (to central part of 1/12 improved
et al. corpus of the penis) on
(1972) 7 days (140–170 kV, 4 mm
Al or l/2 mm Cu plus 1 mm
Al FSD, 40–50 cm)
7 Radiotherapy plus vitamin 3/7 improved
E
Other 335
(continued)
Total #
of
Helvie and 40 900 rad in 5 days (280 kV, 72% relief of pain, 35% decreased 13/16 (81%) who
Ochsner 20 mA, HVL 1.5 mm Cu) size of plaque, and 29% decreased had previously
(1972) Additional treatments of penile angulation received other forms
300 rad at 4–6 weeks to of treatment
max of 2400 rad if clinically improved
warranted
3 patients received
900–1000 rad at 50 kV,
25 mA, HVL, 75 mm Al
Field direct anteroposterior
port with field centered to
plaque
Martin 77 2100 rad in 8 days 26/77 (34%) completely cured
(1972) (200–260 kV) Of remaining: 43/51 (84%) relief of
If no improvement, second pain, 32/51 (63%) improvement of
series in 4–7 months was curvature, and 39/51 (76%)
advised improvement of plaque
Feder 46 600–800 rad in 4 fractions 29/36 (81%) fair-good relief of pain
(1971) over 10 days or 900– 18/46 (39%) fair-good improvement
1200 rad in 6–12 fractions of deformity
over weeks (250 kV, HVL
0.5 mm Cu)
Williams 9 600–1600 rad in 6 days 7/9 improved or cured None showed
and improvement in less
Thomas than 12 months
(1970)
Dunlop and 23 1000 rad in 10 fractions 21/23 (90%) decreased pain and
Lathem overs weeks (220 kV, HVL 15/23 (65%) angulation improved
(1969) 0.5 mm Cu)
Field centered to plaque
Aquino 32 700 rad single dose (Co60) 23/28 (82%) relief of pain
et al. Special cube made of 20/31 (65%) deformity improved
(1967) plaster and bolus material 18/29 (62%) plaque diminished
was used
Griff 17 600–1800 rad in 3–6 8/9 relief of pain
(1967) fractions (250 kV, HVL 3/9 decreased plaque formation
1.85–2.05 mm Cu) or
radium mold treatment of
1500 mg delivering
1200 rad to the skin in 10 h
Duggan 87 800–1000 rad (skin) in 4–5 83% symptoms free or improved Average time for
(1964) fractions (270 kV, 20 mA, improvement was
HVL 1.2 mm Cu). Right 6 months
and left lateral ports, 1 port
treated daily
Second course given in 10
patients (400 rad to 1 port,
600 rad to the other in a
total of 5 days)
Ashworth 8 500 rad single dose repeated 1/8 normal function
(1960) 2–3 times at intervals of a 3/8 relief of pain
few months or 800– 4/8 no benefit
1000 rad in 8–10 weeks
(250 kV)
(continued)
12 Xanthoma, levels, the process consists of histiocytic

Xanthogranuloma proliferation and lipid accumulation. In regard to
the management of these cases, apart from surgi-
Corneal xanthomas appear in association with cal excision, intralesional triamcinolone aceton-
generalized juvenile xanthogranuloma, with dis- ide has been proposed (Hermel et al. 2010). Use
seminated xanthoma, and with generalized his- of radiotherapy has been described, but its benefit
tiocytosis. In the patient with normal cholesterol has not been well established.
Author, year # of cases Treatment Results Notes

Parmley 1 4 Gy radiation to the left anterior eye Tumor recurred
et al. in November 1994, an additional 6 Gy 6 months after last
(1998) in July 1995, and a final third course radiotherapy course
of 6 Gy in December 1995 because of
persistent tumor
Char et al. 1 2250 cGy in 10 fractions over 14 days Abnormalities Remission 2 1/2 years
(1987) by photons to orbit disappeared in after treatment
2 weeks
Liebman 2 400–2000 rad external beam with up Inconclusive with Occurs in association
et al. to 6000 rep strontium regard to response with generalized
(1966) xanthomas and
histiocytosis
Bergink GJ, Deutman AF, van den Broek JFCM et al

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Medical Radiology · Radiation Oncology

Series Editors: Nancy Y. Lee · Jiade J. Lu

The contents range from contemporary statements relating to management

Each volume is a comprehensive reference book on a topical theme, and the

ISSN 0942-5373 ISSN 2197-4187 (electronic)

ISBN 978-3-031-35516-5 ISBN 978-3-031-35517-2 (eBook)

© Springer Nature Switzerland AG 1990, 2003, 2023

Readers of previous editions of Radiation Therapy of Benign Diseases will

As a thought exercise, allow me to share the following abstract:

• Meineke V, Reichrath J, Reinhold U, Tilgen W (2002) Verrucae vulgares

Montreal, QC, Canada David Roberge

Physicians may have obligations related to their professional associations,

Appellate courts have defined malpractice as the failure of a practitioner to

Informed consent is a well-recognized duty and legal obligation of the doctor

Moreover, it also touches the patient’s right to self-determination, to

In the decision of the Supreme Court of Canada, Ciarlariello v. Schacter1, the

 he Uncertainty of a Treatment Effectiveness Proposed by

Medicine changes so fast; new treatments, medications, interventions,

New equipment, tools, techniques, or procedures impact the standard of care.

the physicians acted below the standard of care in administrating radiother-

Radiation Therapy Informed Consent Checklist

The consent should be obtained using simple, lay terminology.

Stanley E. Order MD 1934–2013

Benign Tumors/Premalignant Conditions �������������������������������������������� 229

Jean L. Nakamura, Steve E. Braunstein,

Med Radiol Radiat Oncol (2022) 1

References atric CT scans and subsequent risk of leukaemia and

Radiol 88(1056):20150405. https://doi.org/10.1259/ https://doi.org/10.1182/blood-­2018-­07-­862607. Epub

Contents The goal of this chapter is to compile radiological

1 SI Radiological Units

The currently used metric system of units is

Med Radiol Radiat Oncol (2023) 19

It is important to note that units are often P0 273.2 + T

Table 4 SI radiation quantities and conversion to Gaussian units

Absorbed dose (D) gray [1 Gy = 1 J/kg] Dosage erg 1 Gy = 100 rad

Table 6 Historical radiological units

ICRP (1991) 1990 recommendations of the International

Andrew Martella, Yushen Qian,

Contents 1 Graves’ Ophthalmopathy or

Med Radiol Radiat Oncol (2023) 27

2 Hashimoto’s Thyroiditis against thyroid antigens, diffuse lymphocytic infil-

3 Immunosuppression TLI is an effective and relatively nontoxic

patients 1.6–8.8) lymphoproliferative disorder

simultaneously transplantation with 2 weeks of XRT

3.1 Local Field Irradiation in Renal of immunosuppressive agents. Prospective ran-

4 Lupus Erythematosus (Lupus ticularly in cases refractory to medical man-

Author, Total # of Site and age of

5 Multiple Sclerosis indicates limited benefit of the use of TLI in this

6 Myasthenia Gravis myasthenia gravis include acetylcholinesterase inhib-

7 Granulomatosis frequently granulomatosis with polyangiitis). It is

7.1 Lethal Midline Granuloma

Blizzard RM, Hung W, Chandler RW, Aceto T, Kyle M,

Kolar OJ, Hornback NB (1986. ISSN 0140-6736) related ophthalmopathy. Am J Ophthalmol

Med Radiol Radiat Oncol (2023) 55

Author/year Details Dose/fractionation Results Notes

2 Bowen’s Disease (large lesion, cosmetically or functionally sensi-

Author/year Details Dose/fractionation Results Notes

3 Erythroplasia of Queyrat apy, and topical cytotoxic agents (5-FU,

Author/year Details Dose/fractionation Results Notes

References Guix B, Andres A, Salort P (2008) Keloid and hypertro-

Montreal, QC, Canada David Roberge

he Uncertainty of a Treatment Effectiveness Proposed by

Radiation Therapy Informed Consent Checklist

Benign Tumors/Premalignant Conditions �� 229

Radiol 88(1056):20150405. https://doi.org/10.1259/ https://doi.org/10.1182/blood-2018-07-862607. Epub

1 SI Radiological Units

Contents 1 Graves’ Ophthalmopathy or

2 Hashimoto’s Thyroiditis against thyroid antigens, diffuse lymphocytic infil-

3 Immunosuppression TLI is an effective and relatively nontoxic

3.1 Local Field Irradiation in Renal of immunosuppressive agents. Prospective ran-

4 Lupus Erythematosus (Lupus ticularly in cases refractory to medical man-

5 Multiple Sclerosis indicates limited benefit of the use of TLI in this

6 Myasthenia Gravis myasthenia gravis include acetylcholinesterase inhib-

7 Granulomatosis frequently granulomatosis with polyangiitis). It is

7.1 Lethal Midline Granuloma

2 Bowen’s Disease (large lesion, cosmetically or functionally sensi-

3 Erythroplasia of Queyrat apy, and topical cytotoxic agents (5-FU,

1 Acne oral therapeutics. Although the psychological

1.1 Acne Radiotherapy

2 Carbuncles and Furuncles radiation was thought to be useful in their treat-

2.1 Furuncle Radiotherapy

2.2 Carbuncle Radiotherapy

2.3 Combined Reports of Furuncle and Carbuncle Radiotherapy

3 Fungal Infections/Tinea low-up of 26 years, there was an absolute increase

3.1 Hemoptysis Related to Aspergilloma

3.2 Tinea Capitis

5 Herpes Zoster decrease the duration of symptoms and may

5.1 Herpes Zoster Radiotherapy

6 Ocular Trichiasis epilation, consideration has been given to using

7 Scalp Folliculitis condition with folliculitis and perifolliculitis

7.1 Perifolliculitis Capitis Abscedens et Suffodiens

7.2 Folliculitis Decalvans

8 SARS-CoV-2 included the use of SARS-directed monoclonal

9 Tuberculosis 10 Warts and Condylomas

10.2 Anogenital Warts/Condyloma

2 Pancreatitis and chronic alcohol abuse are implicated in the

2.1 Chronic Pancreatitis

2.2 Acute Pancreatitis

3 Parotitis Latchmore et al. 1940). With doubts on its effi-

3.1 Postoperative Parotitis

3.2 Other Etiologies of Parotitis

4 Pyogenic Granuloma Beyond cessation of an offending drug, a variety

5.1 Central Nervous System (CNS)

5.2 Non-CNS Extrathoracic Involvement

6 Sinusitis have been reported (Calabrese and Dhawan

8 Tonsillitis tumors, and neural tumors (Christensson 1978;

8.1 Historical Examples of Radiotherapy for Tonsillitis

8.2 HIV-Related Tonsillar Hyperplasia

1.1 Prevention of Gynecomastia

1.2 Treatment of Gynecomastia

1.3 Prevention and Treatment

2 Hyperthyroidism safety of RAI, with a focus on its potential carci-

2.1 Selected Studies

2.2 Long-Term Follow-Up Studies

Contents 16 Plantar Fibromatosis, Ledderhose

4 Rheumatoid Arthritis 116

2 Ankylosing Spondylitis aberrations are also reported. It is our opinion

3 Arthritis researchers observed 45% objective improve-